Clinical characteristics: FGFR1-related Hartsfield syndrome comprises two core features: holoprosencephaly (HPE) spectrum disorder and ectrodactyly spectrum disorder.
HPE spectrum disorder, resulting from failed or incomplete forebrain division early in gestation, includes alobar, semilobar, or lobar HPE. Other observed midline brain malformations include corpus callosum agenesis, absent septum pellucidum, absent olfactory bulbs and tracts, and vermian hypoplasia. Other findings associated with the HPE spectrum such as craniofacial dysmorphism, neurologic issues (developmental delay, spasticity, seizures, hypothalamic dysfunction), feeding problems, and endocrine issues (hypogonadotropic hypogonadism and central insipidus diabetes) are common.
Ectrodactyly spectrum disorders are unilateral or bilateral malformations of the hands and/or feet characterized by a median cleft of hand or foot due to absence of the longitudinal central rays (also called split-hand/foot malformation). The number of digits on the right and left can vary. Polydactyly and syndactyly can also be seen.
Diagnosis/testing: The diagnosis of FGFR1-related Hartsfield syndrome is established in a proband with suggestive findings and either an FGFR1 heterozygous pathogenic variant (in those with autosomal dominant inheritance) or FGFR1 biallelic pathogenic variants (in those with autosomal recessive inheritance) identified by molecular genetic testing.
Management: Treatment of manifestations: Diabetes insipidus may require treatment with desmopressin; temperature dysregulation can be managed by modifying the environment; disturbance of sleep-wake cycles can be managed with good sleep hygiene and, if needed, use of melatonin or other sleep aids such as clonidine. Medically refractory epilepsy typically requires multiple anti-seizure medications. Developmental delay is managed with an emphasis on early intervention and an individualized education plan and therapies as needed. Spasticity can be treated with physical and occupational therapy and bracing, as well as muscle relaxants (when moderate or severe). Some children may require a gastrostomy and/or tracheostomy for feeding issues. Cleft lip/palate surgical repair is performed under the direction of a craniofacial team. Hand and foot malformations are managed with therapy and adaptive devices; surgery may be needed to improve dexterity.
Genetic counseling: FGFR1-related Hartsfield syndrome is typically an autosomal dominant (AD) disorder. In two families reported to date, FGFR1-related Hartsfield syndrome was inherited in an autosomal recessive (AR) manner.
AD inheritance. Most probands have a de novo FGFR1 pathogenic variant. Germline mosaicism has been observed in three unrelated families.
AR inheritance. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
Once the FGFR1 pathogenic variant(s) have been identified in an affected family member, prenatal testing and preimplantation genetic testing for a pregnancy at increased risk are possible.
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