Hartsfield syndrome (ORPHA:2117)
A rare, genetic, multiple congenital anomalies syndrome characterized by variable expression of the holoprosencephaly (HPE) spectrum in association with ectrodactyly, cleft lip/palate and/or other ectodermal anomalies. Developmental delay of variable severity and endocrine abnormalities are often associated.
Epidemiology
Approximately 35 patients have been described in the literature to date.
Clinical description
Presentation is heterogeneous; cerebral malformations may present as lobar, semi-lobar and alobar HPE, or milder midline anomalies, such as arhinencephaly, or corpus callosum agenesis. Microcephaly, hypotelorism or hypertelorism, and malformed ears may be observed. Ectrodactyly affects hands and/or feet with variable severity and may involve one to four limbs. Over half of reported individuals have cleft lip and/or palate, which may be uni- or bilateral. Midline brain malformation involving the hypothalamo-pituitary axis may lead a range of endocrine disorders including growth hormone deficiency and subsequent short stature, central diabetes insipidus with a risk of hypernatremic dehydratation, hypogonadotropic hypogonadism, cryptorchidism, micropenis or hypospadias, as well as temperature dysregulation and erratic sleep patterns. Developmental delay is often observed and intellectual disability ranges from mild to severe. In severe cases, individuals are nonverbal, spastic and non-ambulatory. The severity of the neurological impairment in part correlates to the severity of the brain malformation. Seizures are possible. There has been anecdotal reports of skull defects, vertebral anomalies, radial aplasia, eye anomalies, and cardiac malformation.
Etiology
Hartsfield syndrome is most often caused by the presence of heterozygous pathogenic variants in the FGFR1 gene (8p11.23), although bi-allelic pathogenic variants have been described in a minority of patients.
Diagnostic methods
Confirmation of clinical diagnosis is based on FGFR1 sequencing by targeted sanger sequencing, or via NGS (next generation sequencing) multigene panel including FGFR1.
Differential diagnosis
The association of HPE and ectrodactyly is quite unique to Hartsfield syndrome. Phenotypic overlap can be observed in Kallman syndrome, isolated congenital hypogonadotropic hypogonadism, EEC (ectrodactyly ectodermal dysplasia and cleft lip/palate syndrome), HPE, and septo-optic dysplasia spectrum.
Antenatal diagnosis
For parents of an index individual, prenatal diagnosis in subsequent pregnancies should be discussed. Diagnosis involves genetic testing for FGFR1 in the presence of the ultrasound findings of HPE and/or ectrodactyly.
Genetic counseling
Depending on the variants identified, transmission of Hartsfield syndrome can follow an autosomal dominant or recessive mode of inheritance. In most cases, heterozygous FGFR1 variants occur de novo. Several occurrences of parental germline mosaicisms, with recurrences in the sibship, have been reported. Although not known, the recurrence risk in siblings is thus much higher than the usual theoretical 1% estimated risk in the presence of an apparent de novo variant. Recurrence risk is 25% in each pregnancy if bi-allelic variants are identified in the index sib.
Management and treatment
Management and treatment are based on the phenotype. Severity of the HPE must be evaluated by neuroimaging. Spasticity and the possibility of seizures must be assessed. Antiepileptic drugs, physical and occupational therapy may be needed. Nutritional and feeding status should be evaluated. Surgery may be required to treat cleft lip/palate and ectrodactyly. The possibility of endocrine deficiency must be evaluated (growth hormone deficiency, hypogonadotropic hypogonadism, and central diabetes insipidus). Central diabetes insipidus may require treatment with desmopressin.
Prognosis
Prognosis depends on the severity of the phenotype.

                            Last update: 
                            December 2020


                            - Expert reviewer(s): 
                            Pr Catheline VILAIN | ITHACA*


                                * European Reference Network