MedGen

ARCND2B is characterized by the typical features of auriculocondylar syndrome, including the pathognomonic question mark ears, consisting of a variable degree of clefting between the helix and earlobe, as well as hypoplasia of the mandibular condyle, temporomandibular joint abnormalities, micrognathia, microstomia, glossoptosis, and a round facial appearance with prominent cheeks. Patients have difficulty chewing, respiratory abnormalities, snoring, and obstructive and central apneas. In addition, they experience severe gastrointestinal problems, including feeding difficulties with failure to thrive, gastroesophageal reflux, and chronic constipation, and male patients show macropenis whereas female patients may exhibit clitoromegaly (summary by Leoni et al., 2016). Heterozygous mutation in the PLCB4 gene also causes an autosomal dominant form of auriculocondylar syndrome (see ARCND2A, 614669). For a discussion of genetic heterogeneity of auriculocondylar syndrome, see ARCND1 (602483). [from OMIM]

PPP2R5D-related neurodevelopmental disorder is characterized by mild to severe neurodevelopmental delay. Pronounced hypotonia with delay in gross motor skills is common. Onset of independent walking varies widely and ataxia is reported. All reported individuals have speech impairment, with a wide range of abilities. Autism spectrum disorder is reported in six individuals. Macrocephaly is common. Seizures and ophthalmologic abnormalities are reported in fewer than half of individuals. Additional anomalies include skeletal, endocrine, and cardiac malformations, each reported in a few individuals. To date, 23 individuals with PPP2R5D-related neurodevelopmental disorder have been reported. [from GeneReviews]

An instance of renal tubular dysgenesis that is caused by a modification of the individual's genome. [from MONDO]

Lacrimoauriculodentodigital syndrome-1 (LADD1) is a multiple congenital anomaly disorder mainly affecting lacrimal glands and ducts, salivary glands and ducts, ears, teeth, and distal limb segments (summary by Rohmann et al., 2006). Genetic Heterogeneity of Lacrimoauriculodentodigital Syndrome LADD syndrome-2 (LADD2; 620192) is caused by mutation in the FGFR3 gene (134934) on chromosome 4p16, and LADD syndrome-3 (LADD3; 620193) is caused by mutation in the FGF10 gene, an FGFR ligand, on chromosome 5p12. [from OMIM]

Lacrimoauriculodentodigital syndrome-3 (LADD3) is a multiple congenital anomaly disorder characterized by aplasia, atresia or hypoplasia of the lacrimal and salivary systems, cup-shaped ears, hearing loss, and dental and digital anomalies (summary by Milunsky et al., 2006). [from OMIM]

Lacrimoauriculodentodigital syndrome-2 (LADD2) is a multiple congenital anomaly disorder mainly affecting lacrimal glands and ducts, salivary glands and ducts, ears, teeth, and distal limb segments (summary by Rohmann et al., 2006). [from OMIM]

Charcot-Marie-Tooth disease type 1J (CMT1J) is an autosomal dominant sensorimotor peripheral neuropathy characterized by distal muscle weakness and atrophy, as well as distal sensory impairment, predominantly affecting the lower limbs and resulting in gait abnormalities. The age at onset is highly variable, ranging from early childhood to mid-adulthood, and the disorder is progressive, although the severity is also variable. Additional features may include foot deformities, upper limb or hand involvement, and decreased or absent deep tendon reflexes. Electrophysiologic studies tend to show nerve conduction velocities in the demyelinating range, although some patients may have results in the intermediate range, likely reflecting secondary axonal degeneration (summary by Ronkko et al., 2020). For a discussion of genetic heterogeneity of autosomal dominant Charcot-Marie-Tooth disease type 1, see CMT1B (118200). [from OMIM]

Birk-Aharoni syndrome (BKAH) is a severe neurodevelopmental disorder characterized developmental delay, impaired intellectual development, absent speech, spastic tetraplegia with central hypotonia, chorea, inability to walk, hearing loss, micropenis, undescended testes, and mildly elevated liver enzymes (Aharoni et al., 2022). [from OMIM]

Neurodevelopmental disorder with microcephaly, hypotonia, and absent language (NEDMHAL) is a severe autosomal recessive disorder characterized by the constellation of these features. Behavioral problems and hearing loss are also present (Ansar et al., 2020). [from OMIM]

Distal arthrogryposis type 11 (DA11) is an autosomal dominant disorder characterized mainly by camptodactyly. Other features include absent flexion creases and limited forearm supination (Zhou et al., 2019). [from OMIM]

Von Willebrand disease (VWD), a congenital bleeding disorder caused by deficient or defective plasma von Willebrand factor (VWF), may only become apparent on hemostatic challenge, and bleeding history may become more apparent with increasing age. Recent guidelines on VWD have recommended taking a VWF level of 30 or 40 IU/dL as a cutoff for those diagnosed with the disorder. Individuals with VWF levels greater than 30 IU/dL and lower than 50 IU/dL can be described as having a risk factor for bleeding. This change in guidelines significantly alters the proportion of individuals with each disease type. Type 1 VWD (~30% of VWD) typically manifests as mild mucocutaneous bleeding. Type 2 VWD accounts for approximately 60% of VWD. Type 2 subtypes include: Type 2A, which usually manifests as mild-to-moderate mucocutaneous bleeding; Type 2B, which typically manifests as mild-to-moderate mucocutaneous bleeding that can include thrombocytopenia that worsens in certain circumstances; Type 2M, which typically manifests as mild-moderate mucocutaneous bleeding; Type 2N, which can manifest as excessive bleeding with surgery and mimics mild hemophilia A. Type 3 VWD (<10% of VWD) manifests with severe mucocutaneous and musculoskeletal bleeding. [from GeneReviews]

Waardenburg syndrome type 2F (WS2F) is characterized by congenital or neonatal-onset sensorineural hearing loss and altered pigmentation of the iris, hair, and skin. Variable expressivity has been reported, even among patients with the same mutation (Ogawa et al., 2017; Vona et al., 2022). For a general phenotypic description and discussion of genetic heterogeneity of WS2, as well as a brief description of other clinical variants of Waardenburg syndrome (WS1, 193500; WS3, 148820; and WS4, 277580), see WS2A (193510). [from OMIM]

Renal hypodysplasia/aplasia-4 (RHDA4) is characterized by bilateral renal agenesis, with severely reduced to absent amniotic fluid during pregnancy. Patients exhibit the Potter sequence, including flattened nose, ear anomalies, and receding chin, as well as limb contractures and joint dislocations in some patients (Arora et al., 2021; Al-Shamsi et al., 2022). For a general phenotypic description and discussion of genetic heterogeneity of renal hypoplasia/dysplasia, see RHDA1 (191830). [from OMIM]

Noonan syndrome-14 (NS14) is a recessive developmental disorder within the RASopathy clinical spectrum. Patients exhibit developmental delay, impaired intellectual development, and short stature, as well as distinctive dysmorphic features including bitemporal narrowing, hypertelorism, low-set posteriorly rotated ears, prominent nasal bridge, low posterior hairline with a short webbed neck, and pectus excavatum (Motta et al., 2021). For a general phenotypic description and discussion of genetic heterogeneity of Noonan syndrome, see NS1 (163950). [from OMIM]

Developmental and epileptic encephalopathy-101 (DEE101) is a severe autosomal recessive disorder characterized by early infantile epileptic encephalopathy and severe global developmental delay (summary by Blakes et al., 2022). For a general phenotypic description and a discussion of genetic heterogeneity of DEE, see 308350. [from OMIM]

GNB5-related neurodevelopmental disorder (GNB5-NDD) is characterized by a spectrum of neurodevelopmental phenotypes that range from severe-to-profound intellectual disability (ID; 31/41 reported individuals), to mild-to-moderate ID (5/41), to normal intellect with severe language disorder (5/41, one extended family). A unique and specific feature of GNB5-NDD – regardless of neurodevelopmental phenotype – is nearly universal bradycardia caused by sinoatrial node dysfunction (sick sinus syndrome). Most individuals with severe and profound ID have a developmental and epileptic encephalopathy with focal seizures or epileptic spasms, as well as visual impairment (central or retinal) with nystagmus, difficulty feeding, and gastroesophageal reflux disease. The risk of early mortality is increased. [from GeneReviews]

Isolated anhidrosis with normal sweat glands (ANHD) is characterized by absence of perspiration and subsequent heat intolerance with normal morphology and number of sweat glands. Teeth, hair, nails, and skin are normal (Klar et al., 2014). [from OMIM]

Cerebral cavernous malformations (CCMs) are vascular malformations in the brain and spinal cord comprising closely clustered, enlarged capillary channels (caverns) with a single layer of endothelium without mature vessel wall elements or normal intervening brain parenchyma. The diameter of CCMs ranges from a few millimeters to several centimeters. CCMs increase or decrease in size and increase in number over time. Hundreds of lesions may be identified, depending on the person's age and the quality and type of brain imaging used. Although CCMs have been reported in infants and children, the majority become evident between the second and fifth decades with findings such as seizures, focal neurologic deficits, nonspecific headaches, and cerebral hemorrhage. Up to 50% of individuals with FCCM remain symptom free throughout their lives. Cutaneous vascular lesions are found in 9% of those with familial cerebral cavernous malformations (FCCM; see Diagnosis/testing) and retinal vascular lesions in almost 5%. [from GeneReviews]

Neurodevelopmental disorder with hypotonia and dysmorphic facies (NEDHYDF) is characterized by global developmental delay and hypotonia apparent from birth. Affected individuals have variably impaired intellectual development, often with speech delay and delayed walking. Seizures are generally not observed, although some patients may have single seizures or late-onset epilepsy. Most patients have prominent dysmorphic facial features. Additional features may include congenital cardiac defects (without arrhythmia), nonspecific renal anomalies, joint contractures or joint hyperextensibility, dry skin, and cryptorchidism. There is significant phenotypic variability in both the neurologic and extraneurologic manifestations (summary by Tan et al., 2022). [from OMIM]

Developmental delay, impaired speech, and behavioral abnormalities (DDISBA) is characterized by global developmental delay apparent from early childhood. Intellectual disability can range from mild to severe. Additional variable features may include dysmorphic facial features, seizures, hypotonia, motor abnormalities such as Tourette syndrome or dystonia, and hearing loss (summary by Cousin et al., 2021). [from OMIM]