Malpuech facial clefting syndrome
Encyclopedia
Malpuech facial clefting syndrome, also called Malpuech syndrome or Gypsy type facial clefting syndrome, is a rare congenital
syndrome
. It is characterized by facial cleft
ing (any type of cleft in the bones and tissues
of the face, including a cleft lip and palate), a caudal appendage
(a "human tail"), growth deficiency
, intellectual
and developmental disability
, and abnormalities of the renal system (kidneys) and the male genitalia. Abnormalities of the heart, and other skeletal malformations may also be present. The syndrome was initially described by Guilliaume Malpuech and associates in 1983. It is thought to be genetically related to Juberg-Hayward syndrome. Malpuech syndrome has also been considered as part of a spectrum of congenital genetic disorders associated with similar facial, urogenital and skeletal anomalies. Termed "3MC syndrome", this proposed spectrum includes Malpuech, Michels
and Mingarelli-Carnevale (OSA) syndromes. Mutation
s in the COLLEC11 and MASP1
genes are believed to be a cause of these syndromes. The incidence
of Malpuech syndrome is unknown. The pattern of inheritance is autosomal
recessive, which means a defective (mutated) gene associated with the syndrome is located on an autosome, and the syndrome occurs when two copies of this defective gene are inherited.
, including the lips and palate
. The forms of cleft lip and palate typically seen with Malpuech syndrome are midline (down the middle of the lip and palate) or bilateral (affecting both sides of the mouth and palate). Facial clefting generally encompasses a wide range of severity, ranging from minor anomalies such as a bifid (split) uvula, to a cleft lip and palate, to major developmental and structural defects of the facial bones and soft tissues. Clefting of the lip and palate occurs during embryogenesis
. Additional facial and ortho-dental
anomalies that have been described with the syndrome include: hypertelorism
(unusually wide-set eyes, sometimes reported as telecanthus
), narrow palpebral fissure
s (the separation between the upper and lower eyelids) and ptosis
(drooping) of the eyelids, frontal bossing (prominent eyebrow ridge) with synophris
, highly arched eyebrows, wide nasal root and a flattened nasal tip, malar
hypoplasia
(underdeveloped upper cheek bone
), micrognathia
(an undersized lower jaw), and prominent incisor
s. Auditory anomalies include an enlarged ear ridge
, and hearing impairment
associated with congenital otitis media
(or "glue ear", inflammation
of the middle ear
) and sensorineural hearing loss
.
Another feature identified with Malpuech syndrome is a caudal appendage. A caudal appendage is a congenital outgrowth stemming from the coccyx
(tailbone). Present in many non-human animal species as a typical tail
, this feature when seen in an infant has been described as a "human tail". This was observed by Guion-Almeida (1995) in three individuals from Brazil. The appendage on X-rays variously appeared as a prominent protrusion of the coccyx. On a physical examination, the appendage resembles a nodule-like stub of an animal tail.
Deficiencies such as mental retardation, learning disability
, growth retardation
and developmental delay
are common. Psychiatric manifestations that have been reported with the syndrome include psychotic behavior
, obsessive–compulsive disorder, loss of inhibition, hyperactivity, aggression
, fear of physical contact, and compulsive actions like echolalia
(repeating the words spoken by another person). Neuromuscular tic
s have also been noted.
Urogenital abnormalities, or those affecting the urinary
and reproductive system
s, are common with the syndrome. Malpuech et al. (1983) and Kerstjens-Frederikse et al. (2005) reported variously in affected males a micropenis
, hypospadias
(a congenital mislocation of the urinary meatus
), cryptorchidism
(ectopic or undescended testes
), bifid (split) and underdeveloped scrotum
, and an obstructive urethral valve. An affected boy was also reported by Reardon et al. (2001) with left renal agenesis
, an enlarged and downwardly displaced right kidney
, cryptorchidism and a shawl scrotum
. Other malformations that have been noted with the syndrome are omphalocele
and an umbilical hernia
.
Congenital abnormalities of the heart
have also been observed with Malpuech syndrome. From a healthy Japanese couple, Chinen and Naritomi (1995) described the sixth child who had features consistent with the disorder. This two-month-old male infant was also affected by cardiac anomalies including patent ductus arteriosus
(PDA) and ventricular septal defect
. The opening in the ductus arteriosus
associated with PDA had been surgically repaired
in the infant at 38 days of age. A number of minor skeletal aberrations were also reported in the infant, including wormian bones
at the lambdoid suture
s.
similarities with several other genetic disorders. A report by Reardon et al. (2001) of a nine-year-old boy exhibiting facial, caudal and urogenital anomalies consistent with Malpuech syndrome, who also had skeletal malformites indicative of Juberg-Hayward syndrome, suggests that the two disorders may be allelic
(caused by different mutation
s of the same gene
).
Along with several other disorders that have similar, or overlapping features and autosomal recessive inheritance, Malpuech syndrome has been considered to belong under the designation "3MC syndrome". Titomanlio et al. (2005) described a three-year-old female known to have Michels syndrome
. In their review of the physical similarities between Michels, Malpuech and Mingarelli-Carnevale syndromes—particularly the facial appearance including instances of cleft lip and palate, and ptosis, and a similarity of congenital abdominal and urogenital anomalies—they believed the syndromes may represent a spectrum of genetic disorders rather than three individual disorders. They initially suggested this spectrum could be named 3MC (Michels-Malpuech-Mingarelli-Carnevale) syndrome. This conclusion and the name 3MC syndrome was supported by Leal et al. (2008), who reported a brother and sister with an array of symptoms that overlapped the various syndromes. Further assertion of 3MC syndrome was by Rooryck et al. (2011) in an elaboration of its cause.
Malpuech syndrome, as with the other disorders within the 3MC syndrome consideration, is caused by mutations in the COLLEC11 and MASP1
genes. In an investigation by Rooryck et al. (2011), eleven families affected by 3MC syndrome were studied, which resulted in the identification of these two mutations. Both genes encode proteins of the lectin complement pathway
, which plays a role in the complement system
of innate
, or non-specific immunity in humans and other species.
The COLLEC11, or CL-K1 gene is located on the short arm of chromosome
2
(2p25.3) in humans. The CL-K1 protein is a C-type lectin
, and belongs to the collectin
family of these proteins. Other than its role in innate immunity, the protein is thought to be involved in the development of tissues including craniofacial cartilage, the heart and kidney during embryogenesis. This function in facial development was corroborated through study of the zebrafish, where mutations in its version of CL-K1 contributed to craniofacial abnormalities possibly associated with errors in neural crest
cell migration.
The MASP1, or Mannan-binding Serine Protease I gene is located on the long arm of human chromosome 3
at 3q27-q28. The protein is a type of connectin called a mannan-binding lectin
, which plays a role in innate immunity by binding to pathogen
s such as virus
es including HIV
.
As described by Sirmaci et al. (2010), three Turkish individuals from two consanguineous
families (the children of relatives such as cousins are said to be in a consanguineous family) with various characteristics of 3MC syndrome, including facial dysmorphism and a caudal appendage, were evaluated. Investigation of homologous chromosome
s through gene mapping
revealed an autozygous region (a location
on a chromosome where both alleles of a gene originate from a common ancestor) at chromosome 3q27 in both families. In one family, a missense mutation
in MASP1 at this location resulted in the replacement of the amino acid
glycine
by arginine
at position 687 in the gene sequence
. The mutation cosegregated with the observed phenotype. In individuals from the second family, DNA sequencing
of MASP1 showed a nonsense mutation
that resulted in a deactivation of tryptophan
at position 290 in the gene, that also cosegregated with the phenotype. Both mutations occur in a form
of MASP1 known to process IGFBP5
; loss of this function associated with mutation of MASP1 causes disruptions in the availability of insulin-like growth factor
during craniofacial and musculoskeletal development during the embryonic period. These results indicate that mutations in MASP1 are responsible for an array of features found with malformation disorders including Malpuech syndrome.
The syndrome is inherited in an autosomal recessive manner. This means the defective gene(s) responsible for the disorder (COLLEC11, MASP1) is located on an autosome (chromosomes 2 and 3 are autosomes), and two copies of the defective gene (one inherited from each parent) are required in order to be born with the disorder. The parents of an individual with an autosomal recessive disorder both carry
one copy of the defective gene, but usually do not experience any signs or symptoms of the disorder.
for Malpuech syndrome should include cleft lip and/or palate, typical associated facial features, and at least two of the following: urogenital anomalies, caudal appendage, and growth or developmental delay.
Due to the relatively high rate of hearing impairment found with the disorder, it too may be considered in the diagnosis. Another congenital disorder, Wolf-Hirschhorn (Pitt-Rogers-Danks) syndrome, shares Malpuech features in its diagnostic criteria. Because of this lacking differentiation, karyotyping
(microscopic analysis of the chromosomes of an individual) can be employed to distinguish the two. Whereas deletions in the short arm of chromosome 4
would be revealed with Wolf-Hirschhorn, a karyotype without this aberration present would favor a Malpuech syndrome diagnosis. Also, the karyotype of an individual with Malpuech syndrome alone will be normal.
for management of the airway during general anesthesia
can be hampered by the even smaller, or maldeveloped mouth of the infant. For regional anesthesia
, methods like spinal blocking
are more difficult where scoliosis is present. In a 2010 report by Kiernan et al., a four-year-old girl with Malpuech syndrome was being prepared for an unrelated tonsillectomy
and adenoidectomy
. While undergoing intubation, insertion of a laryngoscope
, needed to identify the airway for the placement of the endotracheal tube
, was made troublesome by the presence of micrognathia
attributed to the syndrome. After replacement with a laryngoscope of adjusted size, intubation proceeded normally. Successful general anesthesia followed.
A rare follow-up of a male with Malpuech syndrome was presented by Priolo et al. (2007). Born at term from an uneventful pregnancy and delivery, the infant underwent a surgical repair of a cleft lip and palate. No problems were reported with the procedure. A heart abnormality, atrial septal defect
, was also apparent but required no intervention. At age three years, mental retardation, hyperactivity and obsessive compulsive disorder were diagnosed; hearing impairment was diagnosed at age six, managed with the use of hearing aid
s. Over the course of the decade that followed, a number of psychiatric
evaluations were performed. At age 14, he exhibited a fear of physical contact; at age 15, he experienced a severe psychotic
episode, characterized by agitation and a loss of sociosexual inhibition. This array of symptoms were treated pharmocologically
(with prescription medications). He maintained a low level of mental deficiency by age 17, with moments of compulsive echolalia
.
of Malpuech syndrome has not been determined. A 1999 report by Crisponi et al. suggested that only about 12 individuals worldwide were affected by the disorder at that time. The syndrome was first reported by Guilliaume Malpuech and colleagues in 1983, observed in four children of unspecified gender in what was described as a gypsy family. The children included three siblings and their first cousin; the family was known to be highly consanguineous.
Congenital disorder
A congenital disorder, or congenital disease, is a condition existing at birth and often before birth, or that develops during the first month of life , regardless of causation...
syndrome
Syndrome
In medicine and psychology, a syndrome is the association of several clinically recognizable features, signs , symptoms , phenomena or characteristics that often occur together, so that the presence of one or more features alerts the physician to the possible presence of the others...
. It is characterized by facial cleft
Facial cleft
A facial cleft is an opening or gap in the face, or a malformation of a part of the face. Facial clefts is a collective term for all sorts of clefts. All structures like bone, soft tissue, skin etc. can be affected. Facial clefts are extremely rare congenital anomalies...
ing (any type of cleft in the bones and tissues
Tissue (biology)
Tissue is a cellular organizational level intermediate between cells and a complete organism. A tissue is an ensemble of cells, not necessarily identical, but from the same origin, that together carry out a specific function. These are called tissues because of their identical functioning...
of the face, including a cleft lip and palate), a caudal appendage
Appendage
In invertebrate biology, an appendage is an external body part, or natural prolongation, that protrudes from an organism's body . It is a general term that covers any of the homologous body parts that may extend from a body segment...
(a "human tail"), growth deficiency
Dwarfism
Dwarfism is short stature resulting from a medical condition. It is sometimes defined as an adult height of less than 4 feet 10 inches , although this definition is problematic because short stature in itself is not a disorder....
, intellectual
Mental retardation
Mental retardation is a generalized disorder appearing before adulthood, characterized by significantly impaired cognitive functioning and deficits in two or more adaptive behaviors...
and developmental disability
Developmental disability
Developmental disability is a term used in the United States and Canada to describe lifelong disabilities attributable to mental or physical impairments, manifested prior to age 18. It is not synonymous with "developmental delay" which is often a consequence of a temporary illness or trauma during...
, and abnormalities of the renal system (kidneys) and the male genitalia. Abnormalities of the heart, and other skeletal malformations may also be present. The syndrome was initially described by Guilliaume Malpuech and associates in 1983. It is thought to be genetically related to Juberg-Hayward syndrome. Malpuech syndrome has also been considered as part of a spectrum of congenital genetic disorders associated with similar facial, urogenital and skeletal anomalies. Termed "3MC syndrome", this proposed spectrum includes Malpuech, Michels
Michels syndrome
Michels syndrome is a syndrome characterised by mental deficiency, craniosynostosis, blepharophimosis, ptosis, epicanthus inversus, highly arched eyebrows, and hypertelorism. And vary in other symptoms such as asymmetry of the skull, eyelid, and anterior chamber anomalies, cleft lip and palate,...
and Mingarelli-Carnevale (OSA) syndromes. Mutation
Mutation
In molecular biology and genetics, mutations are changes in a genomic sequence: the DNA sequence of a cell's genome or the DNA or RNA sequence of a virus. They can be defined as sudden and spontaneous changes in the cell. Mutations are caused by radiation, viruses, transposons and mutagenic...
s in the COLLEC11 and MASP1
MASP1 (protein)
Mannan-binding lectin serine protease 1 also known as mannose-associated serine protease 1 is an enzyme that in humans is encoded by the MASP1 gene....
genes are believed to be a cause of these syndromes. The incidence
Incidence (epidemiology)
Incidence is a measure of the risk of developing some new condition within a specified period of time. Although sometimes loosely expressed simply as the number of new cases during some time period, it is better expressed as a proportion or a rate with a denominator.Incidence proportion is the...
of Malpuech syndrome is unknown. The pattern of inheritance is autosomal
Autosome
An autosome is a chromosome that is not a sex chromosome, or allosome; that is to say, there is an equal number of copies of the chromosome in males and females. For example, in humans, there are 22 pairs of autosomes. In addition to autosomes, there are sex chromosomes, to be specific: X and Y...
recessive, which means a defective (mutated) gene associated with the syndrome is located on an autosome, and the syndrome occurs when two copies of this defective gene are inherited.
Characteristics
Malpuech syndrome is congenital, being apparent at birth. It is characterized by a feature known as facial clefting. Observed and noted in the initial description of the syndrome as a cleft lip and palate, facial clefting is identified by clefts in the bones, muscles and tissues of the faceFace
The face is a central sense organ complex, for those animals that have one, normally on the ventral surface of the head, and can, depending on the definition in the human case, include the hair, forehead, eyebrow, eyelashes, eyes, nose, ears, cheeks, mouth, lips, philtrum, temple, teeth, skin, and...
, including the lips and palate
Palate
The palate is the roof of the mouth in humans and other mammals. It separates the oral cavity from the nasal cavity. A similar structure is found in crocodilians, but, in most other tetrapods, the oral and nasal cavities are not truly separate. The palate is divided into two parts, the anterior...
. The forms of cleft lip and palate typically seen with Malpuech syndrome are midline (down the middle of the lip and palate) or bilateral (affecting both sides of the mouth and palate). Facial clefting generally encompasses a wide range of severity, ranging from minor anomalies such as a bifid (split) uvula, to a cleft lip and palate, to major developmental and structural defects of the facial bones and soft tissues. Clefting of the lip and palate occurs during embryogenesis
Embryogenesis
Embryogenesis is the process by which the embryo is formed and develops, until it develops into a fetus.Embryogenesis starts with the fertilization of the ovum by sperm. The fertilized ovum is referred to as a zygote...
. Additional facial and ortho-dental
Orthodontics
Orthodontics, orthodontia, or orthodonture is the first specialty of dentistry that is concerned with the study and treatment of malocclusions , which may be a result of tooth irregularity, disproportionate jaw relationships, or both...
anomalies that have been described with the syndrome include: hypertelorism
Hypertelorism
Hypertelorism is an abnormally increased distance between two organs or bodily parts, usually referring to an increased distance between the orbits . In this condition the distance between the inner eye corners as well as the distance between the pupils is greater than normal...
(unusually wide-set eyes, sometimes reported as telecanthus
Telecanthus
Telacanthus refers to increased distance between the medial canthi of the eyes, while the inter-pupillary distance is normal...
), narrow palpebral fissure
Palpebral fissure
Palpebral fissure is the anatomic name for the separation between the upper and lower eyelids. In adults, this measures about 10mm vertically and 30mm horizontally.It can be reduced in horizontal size by fetal alcohol syndrome and in Williams Syndrome...
s (the separation between the upper and lower eyelids) and ptosis
Ptosis (eyelid)
Ptosis is a drooping of the upper or lower eyelid. The drooping may be worse after being awake longer, when the individual's muscles are tired. This condition is sometimes called "lazy eye", but that term normally refers to amblyopia...
(drooping) of the eyelids, frontal bossing (prominent eyebrow ridge) with synophris
Unibrow
A unibrow is a "confluence of eyebrows"; that is, the presence of abundant hair between the eyebrows, so that they seem to converge to form one long eyebrow. The condition of having a unibrow is synophrys.-Beauty culture:...
, highly arched eyebrows, wide nasal root and a flattened nasal tip, malar
Zygomatic bone
The zygomatic bone is a paired bone of the human skull. It articulates with the maxilla, the temporal bone, the sphenoid bone and the frontal bone. The zygomatic is homologous to the jugal bone of other tetrapods...
hypoplasia
Hypoplasia
Hypoplasia is underdevelopment or incomplete development of a tissue or organ. Although the term is not always used precisely, it properly refers to an inadequate or below-normal number of cells. Hypoplasia is similar to aplasia, but less severe. It is technically not the opposite of hyperplasia...
(underdeveloped upper cheek bone
Maxilla
The maxilla is a fusion of two bones along the palatal fissure that form the upper jaw. This is similar to the mandible , which is also a fusion of two halves at the mental symphysis. Sometimes The maxilla (plural: maxillae) is a fusion of two bones along the palatal fissure that form the upper...
), micrognathia
Micrognathism
Micrognathism is a condition where the jaw is undersized. It is also sometimes called "Mandibular hypoplasia". It is common in infants, but is usually self-corrected during growth, due to the jaws increasing in size. It may be a cause of abnormal tooth alignment and in severe cases can hamper...
(an undersized lower jaw), and prominent incisor
Incisor
Incisors are the first kind of tooth in heterodont mammals. They are located in the premaxilla above and mandible below.-Function:...
s. Auditory anomalies include an enlarged ear ridge
Helix (ear)
The prominent rim of the auricula is called the helix. Where the helix turns downward behind, a small tubercle is frequently seen: the auricular tubercle of Darwin....
, and hearing impairment
Hearing impairment
-Definition:Deafness is the inability for the ear to interpret certain or all frequencies of sound.-Environmental Situations:Deafness can be caused by environmental situations such as noise, trauma, or other ear defections...
associated with congenital otitis media
Otitis media
Otitis media is inflammation of the middle ear, or a middle ear infection.It occurs in the area between the tympanic membrane and the inner ear, including a duct known as the eustachian tube. It is one of the two categories of ear inflammation that can underlie what is commonly called an earache,...
(or "glue ear", inflammation
Inflammation
Inflammation is part of the complex biological response of vascular tissues to harmful stimuli, such as pathogens, damaged cells, or irritants. Inflammation is a protective attempt by the organism to remove the injurious stimuli and to initiate the healing process...
of the middle ear
Middle ear
The middle ear is the portion of the ear internal to the eardrum, and external to the oval window of the cochlea. The mammalian middle ear contains three ossicles, which couple vibration of the eardrum into waves in the fluid and membranes of the inner ear. The hollow space of the middle ear has...
) and sensorineural hearing loss
Sensorineural hearing loss
Sensorineural hearing loss is a type of hearing loss in which the root cause lies in the vestibulocochlear nerve , the inner ear, or central processing centers of the brain....
.
Another feature identified with Malpuech syndrome is a caudal appendage. A caudal appendage is a congenital outgrowth stemming from the coccyx
Coccyx
The coccyx , commonly referred to as the tailbone, is the final segment of the vertebral column. Comprising three to five separate or fused vertebrae below the sacrum, it is attached to the sacrum by a fibrocartilaginous joint, the sacrococcygeal symphysis, which permits limited movement between...
(tailbone). Present in many non-human animal species as a typical tail
Tail
The tail is the section at the rear end of an animal's body; in general, the term refers to a distinct, flexible appendage to the torso. It is the part of the body that corresponds roughly to the sacrum and coccyx in mammals, reptiles, and birds...
, this feature when seen in an infant has been described as a "human tail". This was observed by Guion-Almeida (1995) in three individuals from Brazil. The appendage on X-rays variously appeared as a prominent protrusion of the coccyx. On a physical examination, the appendage resembles a nodule-like stub of an animal tail.
Deficiencies such as mental retardation, learning disability
Learning disability
Learning disability is a classification including several disorders in which a person has difficulty learning in a typical manner, usually caused by an unknown factor or factors...
, growth retardation
Dwarfism
Dwarfism is short stature resulting from a medical condition. It is sometimes defined as an adult height of less than 4 feet 10 inches , although this definition is problematic because short stature in itself is not a disorder....
and developmental delay
Delayed milestone
Delayed milestone, also called developmental delays, is used to describe the condition where a child does not reach one of these stages at the expected age. However, in most cases, a wide variety of ages can be considered normal, and not a cause for medical concern...
are common. Psychiatric manifestations that have been reported with the syndrome include psychotic behavior
Psychosis
Psychosis means abnormal condition of the mind, and is a generic psychiatric term for a mental state often described as involving a "loss of contact with reality"...
, obsessive–compulsive disorder, loss of inhibition, hyperactivity, aggression
Aggression
In psychology, as well as other social and behavioral sciences, aggression refers to behavior between members of the same species that is intended to cause humiliation, pain, or harm. Ferguson and Beaver defined aggressive behavior as "Behavior which is intended to increase the social dominance of...
, fear of physical contact, and compulsive actions like echolalia
Echolalia
Echolalia is the automatic repetition of vocalizations made by another person. It is closely related to echopraxia, the automatic repetition of movements made by another person....
(repeating the words spoken by another person). Neuromuscular tic
Tic
A tic is a sudden, repetitive, nonrhythmic, stereotyped motor movement or vocalization involving discrete muscle groups. Tics can be invisible to the observer, such as abdominal tensing or toe crunching. Common motor and phonic tics are, respectively, eye blinking and throat clearing...
s have also been noted.
Urogenital abnormalities, or those affecting the urinary
Excretory system
The excretory system is a passive biological system that removes excess, unnecessary or dangerous materials from an organism, so as to help maintain homeostasis within the organism and prevent damage to the body. It is responsible for the elimination of the waste products of metabolism as well as...
and reproductive system
Reproductive system
The reproductive system or genital system is a system of organs within an organism which work together for the purpose of reproduction. Many non-living substances such as fluids, hormones, and pheromones are also important accessories to the reproductive system. Unlike most organ systems, the sexes...
s, are common with the syndrome. Malpuech et al. (1983) and Kerstjens-Frederikse et al. (2005) reported variously in affected males a micropenis
Micropenis
Micropenis is an unusually small penis. A common criterion is a dorsal erect penile length of at least 2.5 standard deviations smaller than the mean human penis size. The condition is usually recognized shortly after birth...
, hypospadias
Hypospadias
Hypospadias is a birth defect of the urethra in the male that involves an abnormally placed urinary meatus...
(a congenital mislocation of the urinary meatus
External urethral orifice (male)
The external urethral orifice is the external opening or meatus of the urethra, normally placed at the tip of glans penis; it presents as a vertical slit, possibly bounded on either side by two small labia-like projections, In some cases the slit may be more rounded. This occurs naturally in some...
), cryptorchidism
Cryptorchidism
Cryptorchidism is the absence of one or both testes from the scrotum. It is the most common birth defect regarding male genitalia. In unique cases, cryptorchidism can develop later in life, often as late as young adulthood. About 3% of full-term and 30% of premature infant boys are born with at...
(ectopic or undescended testes
Testicle
The testicle is the male gonad in animals. Like the ovaries to which they are homologous, testes are components of both the reproductive system and the endocrine system...
), bifid (split) and underdeveloped scrotum
Scrotum
In some male mammals the scrotum is a dual-chambered protuberance of skin and muscle containing the testicles and divided by a septum. It is an extension of the perineum, and is located between the penis and anus. In humans and some other mammals, the base of the scrotum becomes covered with curly...
, and an obstructive urethral valve. An affected boy was also reported by Reardon et al. (2001) with left renal agenesis
Renal agenesis
Renal agenesis is a unilateral or bilateral medical condition in which one or both fetal kidneys fail to develop leading to oligohydramnios, resulting in a 40-fold increase in perinatal mortality.It can be associated with RET or UPK3A.-Bilateral:...
, an enlarged and downwardly displaced right kidney
Kidney
The kidneys, organs with several functions, serve essential regulatory roles in most animals, including vertebrates and some invertebrates. They are essential in the urinary system and also serve homeostatic functions such as the regulation of electrolytes, maintenance of acid–base balance, and...
, cryptorchidism and a shawl scrotum
Shawl scrotum
Shawl scrotum is a condition in which the scrotum surrounds the penis, resembling a 'shawl'.It is a characteristic of some syndromes such as Aarskog-Scott syndrome , Rubenstein-Taybi syndrome, craniofrontonasal dysplasia, Hunter Carpenter McDonald Syndrome, Naguib Syndrome, Saito Kuba Tsuruta...
. Other malformations that have been noted with the syndrome are omphalocele
Omphalocele
An omphalocele is a type of abdominal wall defect in which the intestines, liver, and occasionally other organs remain outside of the abdomen in a sac because of a defect in the development of the muscles of the abdominal wall.-Presentation:The sac, which is formed from an outpouching of...
and an umbilical hernia
Umbilical hernia
Congenital umbilical hernia is a congenital malformation, common in infants of African descent. Among adults, it is three times more common in women than in men; among children, the ratio is roughly equal...
.
Congenital abnormalities of the heart
Human heart
The human heart is a muscular organ that provides a continuous blood circulation through the cardiac cycle and is one of the most vital organs in the human body...
have also been observed with Malpuech syndrome. From a healthy Japanese couple, Chinen and Naritomi (1995) described the sixth child who had features consistent with the disorder. This two-month-old male infant was also affected by cardiac anomalies including patent ductus arteriosus
Patent ductus arteriosus
Patent ductus arteriosus is a congenital disorder in the heart wherein a neonate's ductus arteriosus fails to close after birth. Early symptoms are uncommon, but in the first year of life include increased work of breathing and poor weight gain...
(PDA) and ventricular septal defect
Ventricular septal defect
A ventricular septal defect is a defect in the ventricular septum, the wall dividing the left and right ventricles of the heart.The ventricular septum consists of an inferior muscular and superior membranous portion and is extensively innervated with conducting cardiomyocytes.The membranous...
. The opening in the ductus arteriosus
Ductus arteriosus
In the developing fetus, the ductus arteriosus , also called the ductus Botalli, is a shunt connecting the pulmonary artery to the aortic arch. It allows most of the blood from the right ventricle to bypass the fetus's fluid-filled lungs. Upon closure at birth, it becomes the ligamentum arteriosum...
associated with PDA had been surgically repaired
Ligature (medicine)
In surgery or medical procedure, a ligature consists of a piece of thread tied around an anatomical structure, usually a blood vessel or another hollow structure to shut it off. With a blood vessel the surgeon will clamp the vessel perpendicular to the axis of the artery or vein with a hemostat,...
in the infant at 38 days of age. A number of minor skeletal aberrations were also reported in the infant, including wormian bones
Wormian bones
Wormian bones, also known as extra sutural bones are extra bone pieces that occur within a suture in the cranium. These are irregular isolated bones which appear in addition to the usual centers of ossification of the cranium and, although unusual, are not rare. They occur most frequently in the...
at the lambdoid suture
Lambdoid suture
The lambdoid suture is a dense, fibrous connective tissue joint on the posterior aspect of the skull that connects the parietal and temporal bones with the occipital bone.Its name comes from its lambda-like shape....
s.
Classification
Malpuech syndrome has been shown to have physical, or phenotypicalPhenotype
A phenotype is an organism's observable characteristics or traits: such as its morphology, development, biochemical or physiological properties, behavior, and products of behavior...
similarities with several other genetic disorders. A report by Reardon et al. (2001) of a nine-year-old boy exhibiting facial, caudal and urogenital anomalies consistent with Malpuech syndrome, who also had skeletal malformites indicative of Juberg-Hayward syndrome, suggests that the two disorders may be allelic
Allele
An allele is one of two or more forms of a gene or a genetic locus . "Allel" is an abbreviation of allelomorph. Sometimes, different alleles can result in different observable phenotypic traits, such as different pigmentation...
(caused by different mutation
Mutation
In molecular biology and genetics, mutations are changes in a genomic sequence: the DNA sequence of a cell's genome or the DNA or RNA sequence of a virus. They can be defined as sudden and spontaneous changes in the cell. Mutations are caused by radiation, viruses, transposons and mutagenic...
s of the same gene
Gene
A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...
).
Along with several other disorders that have similar, or overlapping features and autosomal recessive inheritance, Malpuech syndrome has been considered to belong under the designation "3MC syndrome". Titomanlio et al. (2005) described a three-year-old female known to have Michels syndrome
Michels syndrome
Michels syndrome is a syndrome characterised by mental deficiency, craniosynostosis, blepharophimosis, ptosis, epicanthus inversus, highly arched eyebrows, and hypertelorism. And vary in other symptoms such as asymmetry of the skull, eyelid, and anterior chamber anomalies, cleft lip and palate,...
. In their review of the physical similarities between Michels, Malpuech and Mingarelli-Carnevale syndromes—particularly the facial appearance including instances of cleft lip and palate, and ptosis, and a similarity of congenital abdominal and urogenital anomalies—they believed the syndromes may represent a spectrum of genetic disorders rather than three individual disorders. They initially suggested this spectrum could be named 3MC (Michels-Malpuech-Mingarelli-Carnevale) syndrome. This conclusion and the name 3MC syndrome was supported by Leal et al. (2008), who reported a brother and sister with an array of symptoms that overlapped the various syndromes. Further assertion of 3MC syndrome was by Rooryck et al. (2011) in an elaboration of its cause.
Cause and genetics
MASP1 (protein)
Mannan-binding lectin serine protease 1 also known as mannose-associated serine protease 1 is an enzyme that in humans is encoded by the MASP1 gene....
genes. In an investigation by Rooryck et al. (2011), eleven families affected by 3MC syndrome were studied, which resulted in the identification of these two mutations. Both genes encode proteins of the lectin complement pathway
Mannan-binding lectin pathway
The Mannan-binding lectin pathway is similar in structure to the classical complement pathway, in that, after activation, it proceeds through the action of C4 and C2 to produce activated complement proteins further down the cascade...
, which plays a role in the complement system
Complement system
The complement system helps or “complements” the ability of antibodies and phagocytic cells to clear pathogens from an organism. It is part of the immune system called the innate immune system that is not adaptable and does not change over the course of an individual's lifetime...
of innate
Innate immune system
The innate immune system, also known as non-specific immune system and secondary line of defence, comprises the cells and mechanisms that defend the host from infection by other organisms in a non-specific manner...
, or non-specific immunity in humans and other species.
The COLLEC11, or CL-K1 gene is located on the short arm of chromosome
Chromosome
A chromosome is an organized structure of DNA and protein found in cells. It is a single piece of coiled DNA containing many genes, regulatory elements and other nucleotide sequences. Chromosomes also contain DNA-bound proteins, which serve to package the DNA and control its functions.Chromosomes...
2
Chromosome 2 (human)
Chromosome 2 is one of the 23 pairs of chromosomes in humans. People normally have two copies of this chromosome. Chromosome 2 is the second largest human chromosome, spanning more than 237 million base pairs and representing almost 8% of the total DNA in cells.Identifying genes on each...
(2p25.3) in humans. The CL-K1 protein is a C-type lectin
C-type lectin
A C-type lectin is a type of carbohydrate-binding protein domain known as a lectin. The C-type designation is from their requirement for calcium for binding. Proteins that contain C-type lectin domains have a diverse range of functions including cell-cell adhesion, immune response to pathogens and...
, and belongs to the collectin
Collectin
Collectins are soluble pattern recognition receptors belonging to the superfamily of collagen containing C-type lectins.Eight collectins have been identified including mannan-binding lectin , surfactant protein A , surfactant protein D , collectin liver 1 , collectin placenta 1 , conglutinin,...
family of these proteins. Other than its role in innate immunity, the protein is thought to be involved in the development of tissues including craniofacial cartilage, the heart and kidney during embryogenesis. This function in facial development was corroborated through study of the zebrafish, where mutations in its version of CL-K1 contributed to craniofacial abnormalities possibly associated with errors in neural crest
Neural crest
Neural crest cells are a transient, multipotent, migratory cell population unique to vertebrates that gives rise to a diverse cell lineage including melanocytes, craniofacial cartilage and bone, smooth muscle, peripheral and enteric neurons and glia....
cell migration.
Chromosome 3 (human)
Chromosome 3 is one of the 23 pairs of chromosomes in humans. People normally have two copies of this chromosome. Chromosome 3 spans almost 200 million base pairs and represents about 6.5 percent of the total DNA in cells....
at 3q27-q28. The protein is a type of connectin called a mannan-binding lectin
Mannan-binding lectin
Mannose-binding lectin , also named mannose- or mannan-binding protein , is an important factor in innate immunity.-Function:MBL belongs to the class of collectins in the C-type lectin superfamily, whose function appears to be pattern recognition in the first line of defense in the pre-immune...
, which plays a role in innate immunity by binding to pathogen
Pathogen
A pathogen gignomai "I give birth to") or infectious agent — colloquially, a germ — is a microbe or microorganism such as a virus, bacterium, prion, or fungus that causes disease in its animal or plant host...
s such as virus
Virus
A virus is a small infectious agent that can replicate only inside the living cells of organisms. Viruses infect all types of organisms, from animals and plants to bacteria and archaea...
es including HIV
HIV
Human immunodeficiency virus is a lentivirus that causes acquired immunodeficiency syndrome , a condition in humans in which progressive failure of the immune system allows life-threatening opportunistic infections and cancers to thrive...
.
As described by Sirmaci et al. (2010), three Turkish individuals from two consanguineous
Consanguinity
Consanguinity refers to the property of being from the same kinship as another person. In that respect, consanguinity is the quality of being descended from the same ancestor as another person...
families (the children of relatives such as cousins are said to be in a consanguineous family) with various characteristics of 3MC syndrome, including facial dysmorphism and a caudal appendage, were evaluated. Investigation of homologous chromosome
Homologous chromosome
Homologous chromosomes are chromosome pairs of approximately the same length, centromere position, and staining pattern, with genes for the same characteristics at corresponding loci. One homologous chromosome is inherited from the organism's mother; the other from the organism's father...
s through gene mapping
Gene mapping
Gene mapping, also called genome mapping, is the creation of a genetic map assigning DNA fragments to chromosomes.When a genome is first investigated, this map is nonexistent. The map improves with the scientific progress and is perfect when the genomic DNA sequencing of the species has been...
revealed an autozygous region (a location
Locus (genetics)
In the fields of genetics and genetic computation, a locus is the specific location of a gene or DNA sequence on a chromosome. A variant of the DNA sequence at a given locus is called an allele. The ordered list of loci known for a particular genome is called a genetic map...
on a chromosome where both alleles of a gene originate from a common ancestor) at chromosome 3q27 in both families. In one family, a missense mutation
Missense mutation
In genetics, a missense mutation is a point mutation in which a single nucleotide is changed, resulting in a codon that codes for a different amino acid . This can render the resulting protein nonfunctional...
in MASP1 at this location resulted in the replacement of the amino acid
Amino acid
Amino acids are molecules containing an amine group, a carboxylic acid group and a side-chain that varies between different amino acids. The key elements of an amino acid are carbon, hydrogen, oxygen, and nitrogen...
glycine
Glycine
Glycine is an organic compound with the formula NH2CH2COOH. Having a hydrogen substituent as its 'side chain', glycine is the smallest of the 20 amino acids commonly found in proteins. Its codons are GGU, GGC, GGA, GGG cf. the genetic code.Glycine is a colourless, sweet-tasting crystalline solid...
by arginine
Arginine
Arginine is an α-amino acid. The L-form is one of the 20 most common natural amino acids. At the level of molecular genetics, in the structure of the messenger ribonucleic acid mRNA, CGU, CGC, CGA, CGG, AGA, and AGG, are the triplets of nucleotide bases or codons that codify for arginine during...
at position 687 in the gene sequence
Messenger RNA
Messenger RNA is a molecule of RNA encoding a chemical "blueprint" for a protein product. mRNA is transcribed from a DNA template, and carries coding information to the sites of protein synthesis: the ribosomes. Here, the nucleic acid polymer is translated into a polymer of amino acids: a protein...
. The mutation cosegregated with the observed phenotype. In individuals from the second family, DNA sequencing
DNA sequencing
DNA sequencing includes several methods and technologies that are used for determining the order of the nucleotide bases—adenine, guanine, cytosine, and thymine—in a molecule of DNA....
of MASP1 showed a nonsense mutation
Nonsense mutation
In genetics, a nonsense mutation is a point mutation in a sequence of DNA that results in a premature stop codon, or a nonsense codon in the transcribed mRNA, and in a truncated, incomplete, and usually nonfunctional protein product. It differs from a missense mutation, which is a point mutation...
that resulted in a deactivation of tryptophan
Tryptophan
Tryptophan is one of the 20 standard amino acids, as well as an essential amino acid in the human diet. It is encoded in the standard genetic code as the codon UGG...
at position 290 in the gene, that also cosegregated with the phenotype. Both mutations occur in a form
Protein isoform
A protein isoform is any of several different forms of the same protein. Different forms of a protein may be produced from related genes, or may arise from the same gene by alternative splicing. A large number of isoforms are caused by single-nucleotide polymorphisms or SNPs, small genetic...
of MASP1 known to process IGFBP5
IGFBP5
Insulin-like growth factor-binding protein 5 is a protein that in humans is encoded by the IGFBP5 gene.-Further reading:...
; loss of this function associated with mutation of MASP1 causes disruptions in the availability of insulin-like growth factor
Insulin-like growth factor
The insulin-like growth factors are proteins with high sequence similarity to insulin. IGFs are part of a complex system that cells use to communicate with their physiologic environment...
during craniofacial and musculoskeletal development during the embryonic period. These results indicate that mutations in MASP1 are responsible for an array of features found with malformation disorders including Malpuech syndrome.
The syndrome is inherited in an autosomal recessive manner. This means the defective gene(s) responsible for the disorder (COLLEC11, MASP1) is located on an autosome (chromosomes 2 and 3 are autosomes), and two copies of the defective gene (one inherited from each parent) are required in order to be born with the disorder. The parents of an individual with an autosomal recessive disorder both carry
Genetic carrier
A genetic carrier , is a person or other organism that has inherited a genetic trait or mutation, but who does not display that trait or show symptoms of the disease. They are, however, able to pass the gene onto their offspring, who may then express the gene...
one copy of the defective gene, but usually do not experience any signs or symptoms of the disorder.
Diagnosis
It is suggested that the diagnostic criteriaMedical diagnosis
Medical diagnosis refers both to the process of attempting to determine or identify a possible disease or disorder , and to the opinion reached by this process...
for Malpuech syndrome should include cleft lip and/or palate, typical associated facial features, and at least two of the following: urogenital anomalies, caudal appendage, and growth or developmental delay.
Due to the relatively high rate of hearing impairment found with the disorder, it too may be considered in the diagnosis. Another congenital disorder, Wolf-Hirschhorn (Pitt-Rogers-Danks) syndrome, shares Malpuech features in its diagnostic criteria. Because of this lacking differentiation, karyotyping
Karyotype
A karyotype is the number and appearance of chromosomes in the nucleus of an eukaryotic cell. The term is also used for the complete set of chromosomes in a species, or an individual organism.p28...
(microscopic analysis of the chromosomes of an individual) can be employed to distinguish the two. Whereas deletions in the short arm of chromosome 4
Chromosome 4 (human)
125px|rightChromosome 4 is one of the 23 pairs of chromosomes in humans. People normally have two copies of this chromosome. Chromosome 4 spans more than 186 million base pairs and represents between 6 and 6.5 percent of the total DNA in cells.Identifying genes on each chromosome is an active area...
would be revealed with Wolf-Hirschhorn, a karyotype without this aberration present would favor a Malpuech syndrome diagnosis. Also, the karyotype of an individual with Malpuech syndrome alone will be normal.
Management
Many of the congenital malformations found with Malpuech syndrome can be corrected surgically. These include cleft lip and palate, omphalocele, urogenital and craniofacial abnormalities, skeletal deformities such as a caudal appendage or scoliosis, and hernias of the umbillicus. The primary area of concern for these procedures applied to a neonate with congenital disorders including Malpuech syndrome regards the logistics of anesthesia. Methods like tracheal intubationTracheal intubation
Tracheal intubation, usually simply referred to as intubation, is the placement of a flexible plastic or rubber tube into the trachea to maintain an open airway or to serve as a conduit through which to administer certain drugs...
for management of the airway during general anesthesia
General anaesthesia
General anaesthesia is a state of unconsciousness and loss of protective reflexes resulting from the administration of one or more general anaesthetic agents...
can be hampered by the even smaller, or maldeveloped mouth of the infant. For regional anesthesia
Regional anaesthesia
Regional anaesthesia is anaesthesia affecting only a large part of the body, such as a limb or the lower half of the body. Regional anaesthetic techniques can be divided into central and peripheral techniques. The central techniques include so called neuraxial blocks...
, methods like spinal blocking
Spinal anaesthesia
Spinal anaesthesia , also called spinal analgesia or sub-arachnoid block , is a form of regional anaesthesia involving injection of a local anaesthetic into the subarachnoid space, generally through a fine needle, usually 9 cm long...
are more difficult where scoliosis is present. In a 2010 report by Kiernan et al., a four-year-old girl with Malpuech syndrome was being prepared for an unrelated tonsillectomy
Tonsillectomy
A tonsillectomy is a 3,000-year-old surgical procedure in which the tonsils are removed from either side of the throat. The procedure is performed in response to cases of repeated occurrence of acute tonsillitis or adenoiditis, obstructive sleep apnea, nasal airway obstruction, snoring, or...
and adenoidectomy
Adenoidectomy
Adenoidectomy is the surgical removal of the adenoids. They may be removed for several reasons, including impaired breathing through the nose and chronic infections or earaches. The surgery is less common for adults. It is most often done on an outpatient basis under general anesthesia....
. While undergoing intubation, insertion of a laryngoscope
Laryngoscopy
Laryngoscopy is a medical procedure that is used to obtain a view of the vocal folds and the glottis. Laryngoscopy may be performed to facilitate tracheal intubation during general anesthesia or cardiopulmonary resuscitation or for procedures on the larynx or other parts of the upper...
, needed to identify the airway for the placement of the endotracheal tube
Tracheal tube
A tracheal tube is a catheter that is inserted into the trachea in order for the primary purpose of establishing and maintaining a patent airway and to ensure the adequate exchange of oxygen and carbon dioxide. Many different types of tracheal tubes are available, suited for different specific...
, was made troublesome by the presence of micrognathia
Micrognathism
Micrognathism is a condition where the jaw is undersized. It is also sometimes called "Mandibular hypoplasia". It is common in infants, but is usually self-corrected during growth, due to the jaws increasing in size. It may be a cause of abnormal tooth alignment and in severe cases can hamper...
attributed to the syndrome. After replacement with a laryngoscope of adjusted size, intubation proceeded normally. Successful general anesthesia followed.
A rare follow-up of a male with Malpuech syndrome was presented by Priolo et al. (2007). Born at term from an uneventful pregnancy and delivery, the infant underwent a surgical repair of a cleft lip and palate. No problems were reported with the procedure. A heart abnormality, atrial septal defect
Atrial septal defect
Atrial septal defect is a form of congenital heart defect that enables blood flow between the left and right atria via the interatrial septum. The interatrial septum is the tissue that divides the right and left atria...
, was also apparent but required no intervention. At age three years, mental retardation, hyperactivity and obsessive compulsive disorder were diagnosed; hearing impairment was diagnosed at age six, managed with the use of hearing aid
Hearing aid
A hearing aid is an electroacoustic device which typically fits in or behind the wearer's ear, and is designed to amplify and modulate sound for the wearer. Earlier devices, known as "ear trumpets" or "ear horns", were passive funnel-like amplification cones designed to gather sound energy and...
s. Over the course of the decade that followed, a number of psychiatric
Psychiatry
Psychiatry is the medical specialty devoted to the study and treatment of mental disorders. These mental disorders include various affective, behavioural, cognitive and perceptual abnormalities...
evaluations were performed. At age 14, he exhibited a fear of physical contact; at age 15, he experienced a severe psychotic
Psychosis
Psychosis means abnormal condition of the mind, and is a generic psychiatric term for a mental state often described as involving a "loss of contact with reality"...
episode, characterized by agitation and a loss of sociosexual inhibition. This array of symptoms were treated pharmocologically
Pharmacology
Pharmacology is the branch of medicine and biology concerned with the study of drug action. More specifically, it is the study of the interactions that occur between a living organism and chemicals that affect normal or abnormal biochemical function...
(with prescription medications). He maintained a low level of mental deficiency by age 17, with moments of compulsive echolalia
Echolalia
Echolalia is the automatic repetition of vocalizations made by another person. It is closely related to echopraxia, the automatic repetition of movements made by another person....
.
Epidemiology and history
The incidenceIncidence (epidemiology)
Incidence is a measure of the risk of developing some new condition within a specified period of time. Although sometimes loosely expressed simply as the number of new cases during some time period, it is better expressed as a proportion or a rate with a denominator.Incidence proportion is the...
of Malpuech syndrome has not been determined. A 1999 report by Crisponi et al. suggested that only about 12 individuals worldwide were affected by the disorder at that time. The syndrome was first reported by Guilliaume Malpuech and colleagues in 1983, observed in four children of unspecified gender in what was described as a gypsy family. The children included three siblings and their first cousin; the family was known to be highly consanguineous.