IllnessMicrocephaly + holoprosencephaly spectrum [including septooptic dysplasia]; differential diagnosis

NGS +

[Sanger]

Holoprosencephaly is a complex brain malformation resulting from incomplete cleavage of the prosencephalon, occurring between the 18th-28th day of gestation. Secondarily the skull is microcephalic and the face may be affected. The severity of holoprosencephaly varies greatly among affected individuals, even within the same family. In the most severe forms, the brain does not divide into hemispheres at all, and cyclopia as well as proboscis may develop. In less severe forms, the brain is partially divided and is associated with hypotelorism. Non-syndromic holoprosencephaly often leads to microcephaly - but may also lead to hydrocephalus with macrocephaly. Other consequences of holoprosencephaly include cleft palate, a single central maxillary incisor and microphthalmia. Most individuals with non-syndromic holoprosencephaly exhibit developmental delay as well as intellectual disability. Affected individuals also often suffer from impaired pituitary function such as diabetes insipidus. Dysfunction in other parts of the brain can lead to seizures, problems regulating body temperature, heart rate and breathing and hyposmia or even anosmia. Mutations in 11 genes are associated with holoprosencephaly according to the German microcephaly guidelines. One quarter of affected individuals have a mutation in one of the genes SHH, ZIC2, SIX3 or TGIF1, while other genes are associated with low proportions. Microcephaly based on holoprosencephaly is often inherited in an autosomal dominant manner. Because many patients do not harbor an identified gene mutation, a negative DNA test result does not exclude the clinical diagnosis.

References: https://www.uptodate.com/contents/microcephaly-a-clinical-genetics-approach

https://www.ncbi.nlm.nih.gov/books/NBK1530/

https://www.ncbi.nlm.nih.gov/books/NBK1334/

• Allelic: Growth hormone deficiency with pituitary anomalies (HESX1)
• Allelic: Hypogonadotropic hypogonadism 2 with/-out anosmia (FGFR1)
• Allelic: Jackson-Weiss syndrome (FGFR1)
• Allelic: Microphthalmia with coloboma 5 (SHH)
• Allelic: Osteoglophonic dysplasia (FGFR1)
• Allelic: Pfeiffer syndrome (FGFR1)
• Allelic: Pituitary hormone deficiency, combined, 5 (HESX1)
• Allelic: Schizencephaly (SHH)
• Allelic: Schizencephaly (SIX3)
• Allelic: Single median maxillary central incisor (SHH)
• Allelic: Trigonocephaly 1 (FGFR1)
• Culler-Jones syndrome [hypopituitarism, mainly GH deficiency and/or postaxial polydactyly] (GLI2)
• Encephalocraniocutaneous lipomatosis, somatic mosaic (FGFR1)
• Hartsfield syndrome [holoprosencephaly, ectrodactyly, cleft/lip palate, mental retardation] (FGFR1)
• Holoprosencephaly 11 (CDON)
• Holoprosencephaly 12, with/-out pancreatic agenesis (CNOT1)
• Holoprosencephaly 12, with/-out pancreatic agenesis (CNOT1) [not in TSO]
• Holoprosencephaly 13 (STAG2)
• Holoprosencephaly 2 (SIX3)
• Holoprosencephaly 3 (SHH)
• Holoprosencephaly 4 (TGIF1)
• Holoprosencephaly 5 (ZIC2)
• Holoprosencephaly 7 (PTCH1)
• Holoprosencephaly 9 (GLI2)
• Holoprosencephaly [Am J Med Genet 154C:52–61, 2010] (DISP1)
• Hypogonadotropic hypogonadism 6 with/-out anosmia
• Joubert syndrome 32 (SUFU)
• Septooptic dysplasia (HESX1)
• Vissers-Bodmer syndrome (CNOT1)