MedGen

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]

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]

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]

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]

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]

Autosomal recessive visceral neuropathy-2 (VSCN2) is characterized by intestinal dysmotility due to aganglionosis or hypoganglionosis of the colon. Patients also exhibit peripheral axonal neuropathy, ptosis, and sensorineural hearing loss (Le et al., 2021). For a discussion of genetic heterogeneity of VSCN, see VSCN1 (243180). [from OMIM]

Familial erythroleukemia is a leukemic or preleukemic state in which red cell proliferation is the predominant feature. Hematologic characteristics include particularly ineffective and hyperplastic erythropoiesis with megaloblastic components accompanied by myeloblastic proliferation of varying degree (Park et al., 2002). Park et al. (2002) discussed the evolution of the definition of 'erythroleukemia,' which is considered by most to be a subtype of acute myelogenous leukemia (AML; 601626). Controversy about the precise definition of erythroleukemia revolves around the number or percentage of erythroblasts and myeloblasts found in the bone marrow and peripheral circulation. In the French-American-British (FAB) classification system (Bennett et al., 1985), it is known as AML-M6, whereas in the revised World Health Organization (WHO) classification system (Harris et al., 1999), it is known as 'AML, not otherwise categorized' (Zini and D'Onofrio, 2004). [from OMIM]

Autosomal recessive primary immunodeficiency-14B (IMD14B) is characterized by onset of recurrent infections in early childhood. Most patients have respiratory infections, but some may develop inflammatory bowel disease or osteomyelitis. Laboratory studies tend to show hypogammaglobulinemia and decreased levels of B cells. Although NK cell and T cell numbers are normal, there may be evidence of impaired immune-mediated cytotoxicity and defective T-cell function (summary by et al., 2018 and et al., 2019). [from OMIM]

Platelet-type bleeding disorder-24 (BDPLT24) is an autosomal dominant form of congenital macrothrombocytopenia associated with platelet anisocytosis. It is a disorder of platelet production. Affected individuals may have no or only mildly increased bleeding tendency. In vitro studies show mild platelet functional abnormalities (summary by Kunishima et al., 2011 and Nurden et al., 2011). For a discussion of genetic heterogeneity of Glanzmann thrombasthenia-like with macrothrombocytopenia, see 187800. [from OMIM]

Glanzmann thrombasthenia-2 (GT2) is an autosomal recessive bleeding disorder characterized by failure of platelet aggregation and by absent or diminished clot retraction. The abnormalities are related to quantitative or qualitative abnormalities of the GPIIb (607759)/IIIa platelet surface fibrinogen receptor complex resulting from mutations in the GPIIIa gene (Rosenberg et al., 1997). For a general phenotypic description and a discussion of genetic heterogeneity of Glanzmann thrombasthenia, see 273800. [from OMIM]

Deafness, cataract, impaired intellectual development, and polyneuropathy (DCIDP) is characterized by early-onset of deafness, cataract, severe developmental delay, and severely impaired intellectual development. Patients later develop polyneuropathy of the lower extremities, associated with depigmentation of the hair in that area (Kroll-Hermi et al., 2020). [from OMIM]