Table 3.

Disorders of Interest in the Differential Diagnosis of Coffin-Lowry Syndrome

Gene / Genetic MechanismDisorderMOIClinical Characteristics / Comment
ATRX Alpha-thalassemia X-linked intellectual disability syndrome XLDistinctive craniofacial features, genital anomalies, hypotonia, mild-to-profound DD/ID. While all affected persons have a normal 46,XY karyotype, genital anomalies comprise a range from hypospadias & undescended testicles, to severe hypospadias & ambiguous genitalia, to normal-appearing female external genitalia. Alpha-thalassemia (~75% of affected persons) is mild & typically does not require treatment.
MED12 FG syndrome type 1 (FGS1) (See MED12-Related Disorders.)XLFGS1 shares w/CLS broad forehead, widely spaced eyes w/downslanted palpebral fissures, thick vermilion of the lower lip, kyphoscoliosis, pectus excavatum, & characteristic behaviors. Unlike CLS, FGS1 is assoc w/disproportionate macrocephaly; constipation that may be assoc w/anal anomalies; broad thumbs & halluces; prominent fingertip pads; & small, rounded, cupped ears that often have overfolded superior helix. Hypotonia often evolves into joint restriction. Partial absence of corpus callosum & fused mammillary bodies are relatively common.
PHF6

Borjeson-Forssman-Lehmann syndrome (BFLS) (OMIM 301900)

XLSevere ID, hand findings similar to those of CLS, short nose w/anteverted nares that may be small w/thick septum, & kyphoscoliosis. Additional findings are large, prominent ears & visual issues. Affected males have extreme hypogonadism & tend to have marked gynecomastia. Females may show partial expression of syndrome.
TCF4 1 Pitt-Hopkins syndrome See footnote 2.Distinctive facial features that become more apparent w/age, significant DD/ID, & episodic hyperventilation &/or breath-holding while awake (~50% of affected persons). Other common findings are behavioral issues, hand stereotypies, seizures, constipation, & severe myopia.
7q11.23 contiguous gene deletion of WBSCR Williams syndrome AD 3In addition to facial findings that may resemble those in CLS, Williams syndrome is assoc w/cardiovascular disease (elastin arteriopathy, peripheral pulmonary stenosis, supravalvar aortic stenosis, hypertension), connective tissue abnormalities, ID (usually mild), a specific cognitive profile, unique personality characteristics, growth abnormalities, & endocrine abnormalities (hypercalcemia, hypercalciuria, hypothyroidism, & early puberty). Feeding difficulties often lead to failure to thrive in infancy.

AD = autosomal dominant; CLS = Coffin-Lowry syndrome; DD = developmental delay; ID = intellectual disability; MOI = mode of inheritance; WBSCR = Williams-Beuren syndrome critical region; XL = X-linked

1.

Pitt-Hopkins syndrome is caused by haploinsufficiency of TCF4 resulting from either a pathogenic variant in TCF4 or a deletion of the chromosome region in which TCF4 is located (18q21.2).

2.

In most affected individuals, Pitt-Hopkins syndrome results from a de novo pathogenic variant or deletion.

3.

Most cases are de novo occurrences, but occasionally parent-to-child transmission is observed.

From: RPS6KA3-Related Intellectual Disability

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