Hamamy et al. (2007) concluded that this was a previously unrecognized autosomal or X-linked recessive syndrome. Mapping In 2 consanguineous families segregating an autosomal recessive craniofacial disorder, 1 of which was originally reported by Hamamy et al. (2007), Bonnard et al. (2012) performed identical-by-descent homozygosity mapping and identified a single 9.2-Mb candidate locus on chromosome 16q12.2-q21. Molecular Genetics In 5 affected individuals from 2 consanguineous families, 1 Turkish and the other a Jordanian family previously reported by Hamamy et al. (2007), with an autosomal recessive craniofacial syndrome mapping to chromosome 16q12.2-q21, Bonnard et al. (2012) screened 73 candidate genes and identified 2 homozygous missense mutations in the IRX5 gene (606195.0001 and 606195.0002) that segregated with disease in each family. They suggested that the disorder be designated 'Hamamy syndrome.' INHERITANCE - Autosomal recessive HEAD & NECK Head - Brachycephaly - Low posterior hair line - Extra frontal hair whorl Face - Bulging midface (in some patients) - Smooth philtrum - Long philtrum - Parotid gland dysfunction (in some patients) - Micrognathia, mild (in some patients) Ears - Hearing loss, sensorineural - Low-set ears - Ear anomalies - Preauricular skin tags (in some patients) Eyes - Severe hypertelorism - Laterally sparse eyebrows - Myopia, progressive severe Nose - Absence or dysfunction of nasolacrimal structures - Broad nasal bridge - Pointed nasal tip - Anteverted nostrils Mouth - High-arched palate - Thin upper vermilion border - Wide mouth Teeth - Loss of lamina dura - Thin or hypoplastic enamel - Worn-out teeth (in some patients) - Malocclusion (in some patients) - Hypodontia (in some patients) Neck - Pterygium colli - Sloping shoulders CARDIOVASCULAR Heart - Intraventricular conduction delay - Mitral regurgitation (in some patients) - Atrial septal defect (in some patients) - Atrioventricular canal, total (in some patients) Vascular - Patent ductus arteriosus, small (in some patients) CHEST Ribs Sternum Clavicles & Scapulae - Pectus excavatum (in some patients) ABDOMEN Gastrointestinal - Swallowing difficulties (in some patients) GENITOURINARY External Genitalia (Male) - Inguinal hernia - Cryptorchidism - Absent gonad activity SKELETAL - Generalized osteopenia Skull - Craniosynostosis (in some patients) Pelvis - Hip dysplasia Limbs - Long bone fractures Hands - Thumb deviation - Ectopic finger creases - Long fingers - Short index finger - Syndactyly (in some patients) - Tapering fingers (in some patients) - Clinodactyly of fifth finger Feet - Long toes (in some patients) SKIN, NAILS, & HAIR Hair - Low posterior hair line - Extra frontal hair whorl NEUROLOGIC Central Nervous System - Psychomotor retardation, moderate VOICE - Unclear speech ENDOCRINE FEATURES - Hypoparathyroidism HEMATOLOGY - Anemia, microcytic hypochromic MOLECULAR BASIS - Caused by mutation in the Iroquois homeobox protein-5 gene (IRX5, 606195.0001 ) ▲ Close
SYNGAP1 -related intellectual disability is a neurological disorder characterized by moderate to severe intellectual disability that is evident in early childhood. The earliest features are typically delayed development of speech and motor skills, such as sitting, standing, and walking. Many people with this condition have weak muscle tone (hypotonia), which contributes to the difficulty with motor skills. Some affected individuals lose skills they had already acquired (developmental regression). Other features of SYNGAP1 -related intellectual disability include recurrent seizures (epilepsy), hyperactivity, and autism spectrum disorder, which is characterized by impaired communication and social interaction; almost everyone with SYNGAP1 -related intellectual disability develops epilepsy, and about half have autism spectrum disorder.
A number sign (#) is used with this entry because autosomal dominant mental retardation-5 (MRD5) is caused by heterozygous mutation in the SYNGAP1 gene (603384) on chromosome 6p21. Almost all reported cases have occurred de novo. Description MRD5 is characterized by moderate to severe intellectual disability with delayed psychomotor development apparent in the first years of life. Most patients develop variable types of seizures, some have autism or autism spectrum disorder (see 209850), and some have acquired microcephaly (summary by Berryer et al., 2013). Clinical Features In 3 of 94 patients with nonsyndromic mental retardation, Hamdan et al. (2009) identified 3 different de novo heterozygous truncating mutations in the SYNGAP1 gene (603384.0001-603384.0003). All patients showed global developmental delay with delayed motor development, hypotonia, moderate to severe mental retardation, and severe language impairment.
They named the condition polyosteolysis-hyperostosis syndrome. The patient shared some features in common with juvenile Paget disease (239000), but direct sequencing of the TNFRSF11B gene (602643) failed to identify a mutation.
This syndrome is characterized by cardiac arrhythmias (ventricular extrasystoles manifesting as bigeminy or multifocal tachycardia with syncopal episodes), perodactyly (hypoplasia and/or agenesis of the distal phalanges of the toes) and Pierre-Robin sequence (see this term).
Toriello (1992) referred to this as heart-hand syndrome V. Mercer et al. (2008) reported a 7-year-old girl who presented with a syncopal episode while swimming and upon examination was found to have a similar facial phenotype, Pierre-Robin sequence, tapering fingers, and multiple ventricular extrasystoles.
A rare genetic multiple congenital anomalies/dysmorphic syndrome characterized by global developmental delay, intellectual disability, absent scrotum or labia majora, absent or underdeveloped nipples and a tuft of hair extruding from the lactiferous ducts, bilateral corneal opacities, and dysmorphic craniofacial features (microcephaly, short forehead, and ear abnormalities, among others).
A rare genetic multiple congenital anomalies/dysmorphic syndrome without intellectual disability characterized by unilateral or bilateral cleft lip and palate and craniofacial dysmorphism (including frontal bossing, hypertelorism, broad flat nasal bridge, cupped ears/thickened helices, and micrognathia).
Short stature-onychodysplasia-facial dysmorphism-hypotrichosis syndrome is a rare, genetic, primary bone dysplasia disorder characterized by severe pre- and post-natal short stature, facial dysmorphism (incl.dolicocephaly, long triangular face, tall forehead, down-slanting palpebral fissures, prominent nose, long philtrum, small ears), early-onset or postpubertal sparse, short hair and hypoplastic fingernails.
A number sign (#) is used with this entry because of evidence that short stature, onychodysplasia, facial dysmorphism, and hypotrichosis (SOFT syndrome) can be caused by homozygous mutation in the POC1A gene (614783) on chromosome 3p21. Description SOFT syndrome is characterized by severely short long bones, peculiar facies associated with paucity of hair, and nail anomalies. ... Mapping Sarig et al. (2012) studied 8 affected members of 2 consanguineous Israeli families of Arab Muslim origin, previously reported by Shalev et al. (2012), who had short stature, onychodysplasia, facial dysmorphism, and hypotrichosis, which Sarig et al. (2012) designated 'SOFT' syndrome. Whole-genome homozygosity mapping revealed 2 chromosomal regions of homozygosity larger than 2 Mb, a 3.7-Mb interval at 4q11 and a 7.3-Mb interval at 3p21.1-p21.31.
A rare syndromic frontonasal dysplasia characterized by distinctive facial dysmorphic features including hypertelorism, almond-shaped palpebral fissures, nasal deformity with creased ridge, depressed or absent tip, and asymmetry and partial absence of nasal bones, and downturned corners of the mouth.
Facial dysmorphism-immunodeficiency-livedo-short stature syndrome is a rare genetic disease characterized by facial dysmorphism with malar hypoplasia and high forehead, immunodeficiency resulting in recurrent infections, impaired growth (with normal growth hormone production and response) resulting in short stature, and livedo affecting face and extremities.
A number sign (#) is used with this entry because of evidence that facial dysmorphism, immunodeficiency, livedo, and short stature (FILS) is caused by homozygous mutation in the POLE gene (174762) on chromosome 12q24. Description FILS syndrome is characterized by mild facial dysmorphism, mainly malar hypoplasia, livedo on the skin since birth, immunodeficiency resulting in recurrent infections, and short stature (summary by Pachlopnik Schmid et al., 2012). ... Noting that the girl had more significantly impaired growth and immunity than the French patients with the same mutation, Thiffault et al. (2015) suggested that rare variants in other POLE subunits or MMR genes might act as genetic modifiers; however, no additional rare variants were detected in MMR genes, POLE1-interacting proteins, or other DNA breakage/instability syndrome genes. INHERITANCE - Autosomal recessive GROWTH Height - Short stature HEAD & NECK Head - Relative macrocephaly Face - Malar hypoplasia - Broad forehead RESPIRATORY - Recurrent respiratory infections SKELETAL Limbs - Bone pain (in some patients) - Bone dysplasia (in some patients) - Lacunar bone lesions (in some patients) - Cortical thickening (in some patients) - Modeling defects at the long bone diaphyses (in some patients) SKIN, NAILS, & HAIR Skin - Livedo - Telangiectasia on the cheeks IMMUNOLOGY - Immunodeficiency - Decreased IgM and IgG2 - Lack of acquired antibodies - Low memory B cells - Low naive T cells - Decreased T cell proliferation MISCELLANEOUS - Onset at birth - One French family has been reported (last curated March 2013) MOLECULAR BASIS - Caused by mutation in the DNA polymerase, epsilon gene (POLE, 174762.0002 ) ▲ Close
A rare genetic multiple congenital anomalies/dysmorphic syndrome characterized by the association of developmental delay, variable intellectual disability, skeletal dysplasia, and in many cases T-cell immunodeficiency and other immunologic abnormalities.
A rare multiple congenital anomalies/dysmorphic syndrome characterized by a large omphalocele containing liver and small intestine, diaphragmatic hernia, cardiovascular anomalies (e. g. aortic coarctation), variable limb malformations (including radioulnar synostosis, agenesis of the radius and/or thumb, generalized syndactyly, and numerical reduction of toes), and dysmorphic facial features.
Devriendt et al. (1999) noted that their patient strongly resembled the sibs reported by Bird et al. (1994) (see DK phocomelia syndrome, 223340). Franceschini et al. (2003) reported 2 sibs, a female fetus and a male fetus, delivered through termination at 23 and 9 weeks of gestation, respectively.
A rare genetic multiple congenital anomalies/dysmorphic syndrome characterized by moderate intellectual disability, dysmorphic facial features (such as prominent glabella, synophrys, and prognathism), generalized hirsutism, bilateral single palmar creases, and seizures.
A rare malformative syndrome with dentinogenesis imperfecta, characterized by dentin dysplasia with opalescent discoloration and severe attrition of primary and permanent teeth, and delayed eruption, bulbous crowns, long and tapered roots, and progressive root canal obliteration of the permanent dentition, associated with proportionate short stature, sensorineural hearing loss, mild intellectual disability, and dysmorphic facial features.
A rare genetic autoinflammatory syndrome with immune deficiency characterized by a combination of autoinflammation, immunodeficiency, and neutrophil dysfunction, as well as mild bleeding diathesis.
A rare multiple congenital anomalies/dysmorphic syndrome with intellectual disability characterized by global developmental delay, intellectual disability, macrothrombocytopenia, lymphedema, and dysmorphic facial features (like synophrys, ptosis, eversion of the lateral portion of the lower eyelid, and thin upper lip, among others).
A number sign (#) is used with this entry because of evidence that Takenouchi-Kosaki syndrome is caused by heterozygous mutation in the CDC42 gene (116952) on chromosome 1p36. Description Takenouchi-Kosaki syndrome is a highly heterogeneous autosomal dominant complex congenital developmental disorder affecting multiple organ systems. ... Some patients have a milder disease course reminiscent of Noonan syndrome (see, e.g., NS1, 163950) (summary by Martinelli et al., 2018). ... There was 1 family (family 30153) in which 3 affected individuals had a milder, but similar phenotype, with features of Noonan syndrome, including pectus deformities and pulmonary stenosis. Inheritance The transmission pattern of Takenouchi-Kosaki syndrome in 1 family (family 30153) reported by Martinelli et al. (2018) was consistent with autosomal dominant inheritance.
Mandibular hypoplasia-deafness-progeroid syndrome is a rare, genetic, premature aging disease characterized by sensorineural deafness, generalized lack of subcutaneous fatty tissue (although with increased truncal deposition) noted from childhood, scleroderma, and facial dysmorphism which includes prominent eyes, a beaked nose, small mouth, crowded teeth and mandibular hypoplasia.
A number sign (#) is used with this entry because mandibular hypoplasia, deafness, progeroid features, and lipodystrophy syndrome (MDPL) is caused by de novo heterozygous mutation in the POLD1 gene (174761) on chromosome 19q13. Description Mandibular hypoplasia, deafness, progeroid features, and lipodystrophy syndrome (MDPL) is an autosomal dominant systemic disorder characterized by prominent loss of subcutaneous fat, a characteristic facial appearance, and metabolic abnormalities including insulin resistance and diabetes mellitus. ... Clinical Features Shastry et al. (2010) reported 7 unrelated patients with a novel syndrome characterized by mandibular hypoplasia, deafness, progeroid features, and lipodystrophy. ... Molecular Genetics In 4 unrelated patients with mandibular hypoplasia, deafness, progeroid features, and lipodystrophy syndrome, Weedon et al. (2013) identified a de novo heterozygous in-frame deletion of residue ser605 in the polymerase active site of the POLD1 gene (174761.0003).
MDP syndrome Other names Mandibular hypoplasia-deafness-progeroid syndrome This condition is inherited in an autosomal dominant manner MDP syndrome , also known as mandibular dysplasia with deafness and progeroid features, is an extremely rare metabolic disorder that prevents fatty tissue from being stored underneath the skin. ... If growth is of concern growth hormone therapy could be considered and coordinated with testosterone replacement where appropriate. [ citation needed ] Deafness [ edit ] Deafness is a feature of MDP syndrome as a result of the nerves not working well and people often have difficulty getting hearing aids because of the small size of their ears. ... Overcrowding can result in the teeth being severely displaced and again it is best to act early because later correction orthodontically can be extremely difficult. [ citation needed ] Development [ edit ] Many people with MDP syndrome are high achievers intellectually following careers in law, medicine and computing. ... "Identification of a novel mutation in the polymerase delta 1 (POLD1) gene in a lipodystrophic patient affected by mandibular hypoplasia, deafness, progeroid features (MDPL) syndrome". Metabolism . 63 (11): 1385–9. doi : 10.1016/j.metabol.2014.07.010 . PMID 25131834 . ^ Shastry S, Simha V, Godbole K, Sbraccia P, Melancon S, Yajnik CS , et al. (2010). "A novel syndrome of mandibular hypoplasia, deafness, and progeroid features associated with lipodystrophy, undescended testes, and male hypogonadism" .
The large number of distinct types of the Ehlers-Danlos syndrome that have already been identified indicates great heterogeneity, but clearly that heterogeneity is not exhausted by the present classification.
Clinical description Skin hyperextensilibity, atrophic scarring, and generalized joint hypermobility are the hallmarks of classical Ehlers-Danlos syndrome (cEDS). However, the clinical picture variably involves multiple organ systems, and clinical presentation may occur anywhere between birth and childhood. ... Differential diagnosis Differential diagnosis is extensive but primarily includes other EDS types (i.e., hypermobile, cardiac-valvular, classical-like type 1, classical-like type 2, spondylodysplastic, vascular, arthrocalasia, kyphoscoliotic, dermatosparaxis EDS), Loeys-Dietz syndromes, Marfan syndrome, cutis laxa, and other inherited connective tissue disorders.
A number sign (#) is used with this entry because Ehlers-Danlos syndrome classic type 2 (EDSCL2) is caused by heterozygous mutation in the collagen alpha-2(V) gene (COL5A2; 120190) on chromosome 2q31. Rarely, specific mutations in the COL1A1 gene (e.g., R134C, 120150.0059) cause classic EDS. Description The Ehlers-Danlos syndromes (EDS) are a group of heritable connective tissue disorders that share the common features of skin hyperextensibility, articular hypermobility, and tissue fragility. The main features of classic Ehlers-Danlos syndrome are loose-jointedness and fragile, bruisable skin that heals with peculiar 'cigarette-paper' scars (Beighton, 1993).
The main features of classic Ehlers-Danlos syndrome are loose-jointedness and fragile, bruisable skin that heals with peculiar 'cigarette-paper' scars (Beighton, 1993). Genetic Heterogeneity of Classic Ehlers-Danlos Syndrome See EDSCL2 (130010), caused by mutation in the COL5A2 gene (120190) on chromosome 2q32. ... Clinical Features Graf (1965) reported a brother and sister with Ehlers-Danlos syndrome who developed 'spontaneous' carotid-cavernous fistula. ... Other Features Deodhar and Woolf (1994) suggested that patients with Ehlers-Danlos syndrome are at unusual risk for postmenopausal osteoporosis. ... EDS XI (147900) is the familial joint instability syndrome. Steinmann et al. (2002) noted that EDS IX (EDS9) and EDS XI (EDS11) have been reclassified as occipital horn syndrome and familial joint hypermobility syndrome, respectively, and that the existence of EDS V (EDS5), EDS VIII (EDS8), and EDS X (EDS10) as distinct entities is questionable.
For a general phenotypic description and a discussion of genetic heterogeneity of FG syndrome, see FGS1 (305450). Mapping Dessay et al. (2002) studied 2 families with FGS, 1 American and 1 English, in which linkage to the FGS1 and FGS2 (300321) loci on the long arm of the X chromosome was excluded.