MedGen

Nail-patella syndrome (NPS) (previously referred to as Fong's disease), encompasses the classic clinical tetrad of changes in the nails, knees, and elbows, and the presence of iliac horns. Nail changes are the most constant feature of NPS. Nails may be absent, hypoplastic, or dystrophic; ridged longitudinally or horizontally; pitted; discolored; separated into two halves by a longitudinal cleft or ridge of skin; and thin or (less often) thickened. The patellae may be small, irregularly shaped, or absent. Elbow abnormalities may include limitation of extension, pronation, and supination; cubitus valgus; and antecubital pterygia. Iliac horns are bilateral, conical, bony processes that project posteriorly and laterally from the central part of the iliac bones of the pelvis. Renal involvement, first manifest as proteinuria with or without hematuria, occurs in 30%-50% of affected individuals; end-stage kidney disease occurs up to 15% of affected individuals. Primary open-angle glaucoma and ocular hypertension occur at increased frequency and at a younger age than in the general population. [from GeneReviews]

Classically, Coffin-Siris syndrome (CSS) was characterized by specific dysmorphic features (coarse facies, sparse scalp hair, thick eyebrows with long lashes, wide nasal bridge with broad nasal tip, anteverted nares with thick ala nasi, wide mouth with thick, everted vermilion of the upper and lower lips, and hypertrichosis), the absence or underdevelopment of the fifth digit finger/toe or nail, learning and developmental differences, and various organ system-related anomalies. As genetic technology has evolved, more individuals with subtle physical exam findings are being diagnosed with CSS. The vast majority of affected individuals have developmental delay / intellectual disability, typically in the moderate-to-severe range, although those with mild cognitive impairment or even normal intelligence have more rarely been described. Most affected individuals have feeding difficulties (with ~25%-50% requiring a feeding tube in childhood, some of whom then outgrow it), hypotonia, and frequent infections. About half of affected individuals have epilepsy. Other findings may include skeletal features (joint laxity, scoliosis), hearing impairment (both conductive and sensorineural), eye issues (ptosis, strabismus), congenital heart defects, genitourinary malformations, and behavioral issues (including hyperactivity and/or aggressiveness). [from GeneReviews]

Epidermolysis bullosa with pyloric atresia (EB-PA) is characterized by fragility of the skin and mucous membranes, manifested by blistering with little or no trauma; congenital pyloric atresia; renal and/or ureteral anomalies; and protein-losing enteropathy. The course of EB-PA is usually severe and most often lethal in the neonatal period. Those who survive may have severe blistering with formation of granulation tissue on the skin around the mouth, nose, diaper area, fingers, and toes, and internally around the trachea. However, some affected individuals have little or no blistering later in life. Additional features shared by EB-PA and the other major forms of epidermolysis bullosa (EB) include congenital localized absence of skin (aplasia cutis congenita) affecting the extremities and/or head, milia, nail dystrophy, scarring alopecia, hypotrichosis, and corneal abnormalities. [from GeneReviews]

Fryns syndrome is characterized by diaphragmatic defects (diaphragmatic hernia, eventration, hypoplasia, or agenesis); characteristic facial appearance (coarse facies, wide-set eyes, a wide and depressed nasal bridge with a broad nasal tip, long philtrum, low-set and anomalous ears, tented vermilion of the upper lip, wide mouth, and a small jaw); short distal phalanges of the fingers and toes (the nails may also be small); pulmonary hypoplasia; and associated anomalies (polyhydramnios, cloudy corneas and/or microphthalmia, orofacial clefting, renal dysplasia / renal cortical cysts, and/or malformations involving the brain, cardiovascular system, gastrointestinal system, and/or genitalia). Survival beyond the neonatal period is rare. Data on postnatal growth and psychomotor development are limited; however, severe developmental delay and intellectual disability are common. [from GeneReviews]

TBC1D24-related disorders comprise a continuum of features that were originally described as distinct, recognized phenotypes: DOORS syndrome (deafness, onychodystrophy, osteodystrophy, mental retardation, and seizures), with profound sensorineural hearing loss, onychodystrophy, osteodystrophy, intellectual disability / developmental delay, and seizures; familial infantile myoclonic epilepsy (FIME), with early-onset myoclonic seizures, focal epilepsy, dysarthria, and mild-to-moderate intellectual disability; progressive myoclonus epilepsy (PME), with action myoclonus, tonic-clonic seizures, ataxia, and progressive neurologic decline; rolandic epilepsy with paroxysmal exercise-induced dystonia and writer's cramp (EPRPDC); developmental and epileptic encephalopathy (DEE), including epilepsy of infancy with migrating focal seizures (EIMFS); autosomal recessive nonsyndromic hearing loss (DFNB); and autosomal dominant nonsyndromic hearing loss (DFNA). [from GeneReviews]

The TP63-related disorders comprise six overlapping phenotypes: Ankyloblepharon-ectodermal defects-cleft lip/palate (AEC) syndrome (which includes Rapp-Hodgkin syndrome). Acro-dermo-ungual-lacrimal-tooth (ADULT) syndrome. Ectrodactyly, ectodermal dysplasia, cleft lip/palate syndrome 3 (EEC3). Limb-mammary syndrome. Split-hand/foot malformation type 4 (SHFM4). Isolated cleft lip/cleft palate (orofacial cleft 8). Individuals typically have varying combinations of ectodermal dysplasia (hypohidrosis, nail dysplasia, sparse hair, tooth abnormalities), cleft lip/palate, split-hand/foot malformation/syndactyly, lacrimal duct obstruction, hypopigmentation, hypoplastic breasts and/or nipples, and hypospadias. Findings associated with a single phenotype include ankyloblepharon filiforme adnatum (tissue strands that completely or partially fuse the upper and lower eyelids), skin erosions especially on the scalp associated with areas of scarring, and alopecia, trismus, and excessive freckling. [from GeneReviews]

Lethal acantholytic epidermolysis bullosa (EBLA) is an autosomal recessive skin disorder characterized by extensive epidermal dislodgment, universal alopecia, and anonychia. Cardiac involvement may be present. Death occurs in the neonatal period (summary by Hobbs et al., 2010). [from OMIM]

Multiple synostoses syndrome is characterized by multiple joint fusions, usually commencing in the hands, conductive deafness, and characteristic facial features, including a broad, tubular-shaped nose and a thin upper vermilion. Other features include brachydactyly, hypoplastic or absent middle phalanges, radial head dislocation, and pectus carinatum (summary by Takahashi et al., 2001). Genetic Heterogeneity of Multiple Synostoses Syndrome Other forms of multiple synostoses syndrome include SYNS2 (610017), caused by mutation in the GDF5 gene (601146) on chromosome 20q11; SYNS3 (612961), caused by mutation in the FGF9 gene (600921) on chromosome 13q12; and SYNS4 (617898), caused by mutation in the GDF6 gene (601147) on chromosome 8q22. [from OMIM]

Congenital anonychia is defined as the absence of fingernails and toenails. Anonychia and its milder phenotypic variant, hyponychia, usually occur as a feature of genetic syndromes, in association with significant skeletal and limb anomalies. Isolated nonsyndromic congenital anonychia/hyponychia is a rare entity that usually follows autosomal recessive inheritance with variable expression, even within a given family. The nail phenotypes observed range from no nail field to a nail field of reduced size with an absent or rudimentary nail (summary by Bruchle et al., 2008). This form of nail disorder is referred to here as nonsyndromic congenital nail disorder-4 (NDNC4). For a list of other nonsyndromic congenital nail disorders and a discussion of genetic heterogeneity, see NDNC1 (161050). [from OMIM]

Bartsocas-Papas syndrome-1 (BPS1) is an autosomal recessive disorder characterized by multiple popliteal pterygia, ankyloblepharon, filiform bands between the jaws, cleft lip and palate, and syndactyly. Early lethality is common, although survival into childhood and beyond has been reported (summary by Mitchell et al., 2012). Genetic Heterogeneity of Bartsocas-Papas Syndrome Bartsocas-Papas syndrome-2 (BPS2) is caused by mutation in the CHUK gene (600664). A less severe form of popliteal pterygium syndrome (PPS; 119500) is caused by mutation in the IRF6 gene (607199). [from OMIM]

Yunis-Varon syndrome (YVS) is a severe autosomal recessive disorder characterized by skeletal defects, including cleidocranial dysplasia and digital anomalies, and severe neurologic involvement with neuronal loss. Enlarged cytoplasmic vacuoles are found in neurons, muscle, and cartilage. The disorder is usually lethal in infancy (summary by Campeau et al., 2013). [from OMIM]

A rare subtype of brachydactyly type B characterized by hypoplasia or aplasia of the distal phalanges of digits 2-5 with or without nail dysplasia, in association with fusion of the middle and distal phalanges, a broad or bifid thumb, and occasionally distal and proximal symphalangism or syndactyly. The feet are less severely affected than the hands. [from ORDO]

The Al-Awadi/Raas-Rothschild/Schinzel phocomelia syndrome (AARRS) is a rare autosomal recessive disorder characterized by severe malformations of upper and lower limbs with severely hypoplastic pelvis and abnormal genitalia. The disorder is believed to represent a defect of dorsoventral patterning and outgrowth of limbs (summary by Kantaputra et al., 2010). Overlapping limb reduction syndromes, less severe in nature, that are also caused by homozygous mutation in the WNT7A gene include Fuhrmann syndrome (228930), characterized by fibular aplasia or hypoplasia, femoral bowing, and poly-, syn-, and oligodactyly, and Santos syndrome (228930), characterized by fibular agenesis/hypoplasia, oligodactylous clubfeet, and anonychia/nail hypoplasia. Al-Qattan et al. (2013) stated that AARRS and Fuhrmann syndrome can be differentiated by the following features, which are seen only in AARRS: complete aplasia of 1 or both lower limbs, and absent elbow with radiohumeral synostosis. In addition, the number of digits per hand is 1 to 3 in AARRS, whereas there are 4 to 5 digits in Fuhrmann syndrome. 'Phocomelia' refers to an intercalary limb defect with the hand or foot being directly attached to the humerus or femur (absent zeugopod) or directly attached to the trunk (absent stylopod and zeugopod). AlQattan et al. (2013) stated that the limb defect observed in Schinzel phocomelia syndrome represents 'true' phocomelia, whereas the limb defect in AARRS is an 'apparent' phocomelia, in which there is absent ulna with radiohumeral synostosis. The authors described 3 radiologic features that define 'apparent' phocomelia: a single arm/forearm bone that appears too long to be the humerus alone; a thicker cortex at the area of the radiohumeral synostosis, with or without slight angulation at the site of synostosis; and the apparently single bone resembling the humerus proximally and the radius distally. The authors also noted that phocomelia is not a feature of the allelic disorder Fuhrmann syndrome (228930). Other distinguishing features of Schinzel phocomelia syndrome include normal nails and dorsal hand skin; distoproximal gradient of lower limb defects, without a resultant stick-like appearance; and a characteristic large cranial defect. AlQattan et al. (2013) concluded that Schinzel phocomelia syndrome and AARRS are distinct phenotypes. [from OMIM]

Zimmermann-Laband syndrome is a rare disorder characterized by gingival fibromatosis, dysplastic or absent nails, hypoplasia of the distal phalanges, scoliosis, hepatosplenomegaly, hirsutism, and abnormalities of the cartilage of the nose and/or ears (summary by Balasubramanian and Parker, 2010). Genetic Heterogeneity of Zimmermann-Laband Syndrome ZLS2 (616455) is caused by mutation in the ATP6V1B2 gene (606939) on chromosome 8p21. ZLS3 (618658) is caused by mutation in the KCNN3 gene (602983) on chromosome 1q21. [from OMIM]

Odontoonychodermal dysplasia (OODD) is an autosomal recessive disorder characterized by dry hair, severe hypodontia, smooth tongue with marked reduction of fungiform and filiform papillae, onychodysplasia, hyperkeratosis of the palms and soles, hypo- and hyperhidrosis of the skin, and atrophic patches on the face (summary by Adaimy et al., 2007; Yu et al., 2019). [from OMIM]

SLC25A24 Fontaine progeroid syndrome is a multisystem connective tissue disorder characterized by poor growth, abnormal skeletal features, and distinctive craniofacial features with sagging, thin skin, and decreased subcutaneous fat suggesting an aged appearance that is most pronounced in infancy and improves with time. Characteristic radiographic features include turribrachycephaly with widely open anterior fontanelle, craniosynostosis, and anomalies of the terminal phalanges. Cardiovascular, genitourinary, ocular, and gastrointestinal abnormalities may also occur. To date, 13 individuals with a molecularly confirmed diagnosis of SLC25A24 Fontaine progeroid syndrome have been described. [from GeneReviews]

Cenani-Lenz syndactyly syndrome (CLSS) is an autosomal recessive disorder characterized mainly by anomalies of distal limb development, with fusion and disorganization of metacarpal and phalangeal bones, radius and ulnar shortening, radioulnar synostosis, and severe syndactyly of hands and feet. Mild facial dysmorphism is present in most patients. Kidney anomalies, including renal agenesis and hypoplasia, occur in over half of patients (summary by Li et al., 2010). [from OMIM]

Jawad syndrome (JWDS) is an autosomal recessive disorder characterized by congenital microcephaly, moderately to severely impaired intellectual development, and digital malformations including phalangeal joint swelling, clinodactyly, polydactyly, syndactyly, and total absence of nails (summary by Qvist et al., 2011). [from OMIM]

Zimmerman-Laband syndrome is a developmental disorder characterized by facial dysmorphism with gingival enlargement, bulbous soft nose, and think floppy ears, nail aplasia or hypoplasia, hypertrichosis, joint hypertextensibility, hepato(spleno)megaly, and impaired intellectual development with or without epilepsy (summary by Kortum et al., 2015). For a general phenotypic description and a discussion of genetic heterogeneity of Zimmermann-Laband syndrome, see ZLS1 (135500). [from OMIM]

A rare genetic ectodermal dysplasia syndrome characterized by short stature, nail dystrophy and/or nail loss, oral mucosa and/or tongue hyperpigmentation, dentition abnormalities (delayed teeth eruption, hypodontia, enamel hypoplasia), keratoderma on the margins of the palms and soles and focal hyperkeratosis on the dorsum of the hands and feet. Additionally, dysphagia with esophageal strictures, sensorineural deafness, bronchial asthma and severe iron-deficiency anemia have also been observed. [from SNOMEDCT_US]