Septooptic Dysplasia

A number sign (#) is used with this entry because of evidence that septooptic dysplasia can be caused by mutation in the homeobox gene HESX1 (601802) on chromosome 3p14.

Mutation in the HESX1 gene can also cause combined pituitary hormone deficiency-5 (CPHD5), without associated optic nerve hypoplasia or defects of midline brain structures. For a discussion of phenotypic and genetic heterogeneity of CPHD, see CPHD1 (613038).

Growth hormone deficiency with pituitary anomalies can also be caused by mutation in the HESX1 gene.

Description

Septooptic dysplasia is a clinically heterogeneous disorder loosely defined by any combination of optic nerve hypoplasia, pituitary gland hypoplasia, and midline abnormalities of the brain, including absence of the corpus callosum and septum pellucidum (Dattani et al., 1998). The diagnosis of this rare congenital anomaly is made when 2 or more features of the classic triad are present. Approximately 30% of patients have complete manifestations, 62% display hypopituitarism, and 60% have an absent septum pellucidum. The disorder is equally prevalent in males and females and is more common in infants born to younger mothers, with a reported incidence of 1 in 10,000 live births (summary by Webb and Dattani, 2010).

Also see 516020.0012 for a form of septooptic dysplasia associated with cardiomyopathy and exercise intolerance.

Clinical Features

According to Rush and Bajandas (1978), the term 'septooptic dysplasia' was coined in 1956 by de Morsier, who pointed out the association of optic nerve hypoplasia and absence of the septum pellucidum. Hoyt et al. (1970) reported the association of pituitary dwarfism. Brook et al. (1972) described 4 unrelated children with hypoplastic optic nerves, absent septum pellucidum, and endocrinologic abnormalities. Harris and Haas (1972) noted that septooptic dysplasia is characterized by hypoplastic optic discs with characteristic double margin, an absent septum pellucidum, and growth hormone (GH; 139250) deficiency. Harris and Haas (1972) stated that there was no evidence for a mendelian basis for septooptic dysplasia syndrome.

Benner et al. (1990) reported one of the few familial occurrences: a brother and sister had features of septooptic dysplasia including bilateral optic nerve hypoplasia, absent septum pellucidum, and partial pituitary insufficiency. Additionally, midline central nervous system abnormalities of the corpus callosum and cerebellum were demonstrated. The posterior fossa changes suggested a variant of the Dandy-Walker syndrome (220200).

Willnow et al. (1996) reported studies on 18 patients with septooptic dysplasia. CCT or MRI yielded the following results: 4 patients had cavum septum pellucidum, 3 patients had hypoplasia of the cerebellum, 1 had aplasia of the corpus callosum, and 1 had aplasia of the fornix. An empty sella with or without an ectopic pituitary was seen in 4 cases. Severe psychomotor retardation was present in 14 of the 18 patients. All patients had short stature. Head circumference and weight were within normal limits. A high prevalence of pituitary dysfunction was revealed, most commonly GH deficiency and failure of the pituitary to respond to thyrotropin releasing hormone (TSH; 613879).

Wales and Quarrell (1996) described a sister and brother from a consanguineous mating in whom septooptic dysplasia was present, suggesting mendelian inheritance. The female was born with dislocation of the hip and talipes equinovarus. Hypoglycemia developed at 7 hours, at which time blood tests revealed undetectable levels of GH, adrenocorticotropic hormone (ACTH), luteinizing hormone (LH; 152780), and follicle-stimulating hormone (FSH; 136530). Anterior pituitary hormone replacement therapy was begun at 7 days and she remained well subsequently. CT scan of the brain demonstrated absent septum pellucidum and corpus callosum. Vision and optic disc examination were normal at 18 months. At birth, the male was found to have micropenis and cryptorchidism, and hypoglycemia was detected at 4 hours of age. There were no other congenital abnormalities. Because of low hormone levels, full anterior pituitary hormone replacement was started on the first day. He subsequently developed profound but transient hypocalcemia which responded to calcium and vitamin D supplements. Repeat CT scanning showed absence of the septum pellucidum and corpus callosum. A double second-cousin had nesidioblastosis (256450), a probably unrelated disorder (see also craniotelencephalic dysplasia, 218670). Brain imaging of the affected sibs by Brickman et al. (2001) showed undescended or ectopic posterior pituitary.

Brodsky et al. (1997) described sudden and unexpected death in 5 children with septooptic dysplasia. All children had corticotropin deficiency, all had thermoregulatory disturbances, and 4 children had diabetes insipidus. In at least 4 children, clinical deterioration was caused by fever and dehydration from a presumed viral illness, which appeared to precipitate adrenal crisis.

Thomas et al. (2001) noted that the septooptic dysplasia phenotype is highly variable, with 62% of affected individuals having associated hypopituitarism and 30% displaying all 3 manifestations, including optic nerve hypoplasia and agenesis of midline structures.

In a study group comprising 55 optic nerve hypoplasia patients, Birkebaek et al. (2003) reported that 49% had an abnormal septum pellucidum on MRI, and 64% had a hypothalamic-pituitary axis abnormality. Twenty-seven patients (49%) had endocrine dysfunction, and 23 of these had hypothalamic-pituitary axis abnormality. The frequency of endocrinopathy was higher in patients with an abnormal septum pellucidum (56%) than a normal septum pellucidum (39%). Patients were divided into 4 groups based on septum pellucidum and hypothalamic-pituitary axis appearance: (1) both normal; (2) abnormal septum pellucidum and normal hypothalamic-pituitary axis; (3) normal septum pellucidum and abnormal hypothalamic-pituitary axis; and (4) both abnormal. The frequency of multiple pituitary hormone deficiency was highest (56%) in group 4, lower (35%) in group 3, and even lower (22%) in group 2. Precocious puberty was most common in group 2. None of the patients in group 1 had endocrine dysfunction. The authors concluded that septum pellucidum and hypothalamic-pituitary axis appearances on MRI can be used to predict the likely spectrum of endocrinopathy.

Stevens and Dobyns (2004) reported a boy with optic nerve hypoplasia, pituitary dysfunction, and MRI findings consistent with septooptic dysplasia, who also had multiple limb defects suggestive of amniotic bands. The authors reviewed 5 similar cases from the literature and concluded that there is evidence for a vascular pathogenesis of septooptic dysplasia in some patients. Harrison et al. (2004) reported another male infant with septooptic dysplasia and limb malformations, including syndactyly of several fingers and toes, hypoplastic digits, and ring constriction of at least 1 finger. He had bilateral hypoplastic optic nerves, absence of the septum pellucidum, and colpocephaly with a normal pituitary-hypothalamic axis.

McNay et al. (2007) studied 210 patients with septooptic dysplasia for whom detailed clinical information was available and stated that 60 (29%) of the patients displayed the full spectrum (optic nerve hypoplasia (ONH), midline forebrain defects, and hypopituitarism), whereas 2 of the 3 features were present in 150 (71%) of the patients: 38 (18%) had ONH and midline defects, 83 (39%) had ONH and hypopituitarism, and 29 (14%) had hypopituitarism and midline defects.

Webb and Dattani (2010) reviewed septooptic dysplasia, noting that there is a wide variation in the severity of the clinical features found and in their association with other diagnoses, which follows no clear pattern. The main reported clinical findings are hypopituitarism (62% to 80%), with growth hormone deficiency being the commonest endocrine abnormality; visual impairment, which is severe in 23% of patients; and developmental delay, which is more common in children with bilateral (57%) than unilateral (32%) optic nerve hypoplasia. Seizures, developmental delay, and cerebral palsy are the most frequent neurologic associations.

Molecular Genetics

In 2 sibs with septooptic dysplasia reported by Wales and Quarrell (1996), Dattani et al. (1998) demonstrated homozygosity for a missense mutation in the HESX1 gene (601802.0001). Genetic analysis of the HESX1 gene in 18 patients with sporadic septooptic dysplasia revealed no abnormalities, suggesting that mutations in the HESX1 gene are not a frequent occurrence in sporadic disease.

Thomas et al. (2001) scanned for HESX1 mutations in 228 patients with a broad spectrum of congenital pituitary defects, ranging in severity from isolated growth hormone deficiency to septooptic dysplasia with panhypopituitarism. The authors identified heterozygosity for 3 different missense mutations, respectively, in 2 brothers with GH deficiency, 1 of whom also had optic nerve hypoplasia (601802.0002), an unrelated girl with GH deficiency and pituitary anomalies (601802.0003), and a boy with combined pituitary hormone deficiency (CPHD) involving GH, thyrotropin (TSH; 188540), LH, and FSH, without optic nerve hypoplasia or midline brain defects (601802.0010). All 3 mutations had been inherited from an unaffected parent, and in 1 pedigree, an unaffected sib also carried the mutation, indicating incomplete penetrance; the mutations were not found in 100 control chromosomes. Thomas et al. (2001) hypothesized that some sporadic cases of the more common mild forms of pituitary hypoplasia have a genetic basis, resulting from heterozygous mutations in the HESX1 gene.

In a Japanese patient with sporadic pituitary and optic nerve hypoplasia, Tajima et al. (2003) identified a heterozygous insertion mutation in the HESX1 gene (601802.0004).

In a patient with combined pituitary hormone deficiency, but without optic nerve hypoplasia, Carvalho et al. (2003) identified a homozygous mutation in the HESX1 gene (601802.0005).

Sobrier et al. (2006) reported 2 unrelated Italian patients with panhypopituitarism who, at birth, presented with hypoglycemic seizures and respiratory distress complicated by shock, in a familial context of neonatal death in 1 family. MRI exam showed anterior pituitary aplasia in a flat sella turcica and a normally located posterior pituitary without optic nerve hypoplasia in both patients. Sequencing of HESX1 exons and their flanking intronic regions revealed homozygosity for a frameshift mutation (601802.0007) and a splice defect (601802.0008), respectively.

Heterogeneity

McNay et al. (2007) determined the contribution of HESX1 genetic defects to the etiology of hypopituitarism. Nonfamilial patients (724) with either septooptic dysplasia (314 patients) or isolated pituitary dysfunction, optic nerve hypoplasia, or midline neurologic abnormalities (410 patients) originally screened by SSCP were rescreened by heteroduplex detection for mutations in the coding and regulatory regions of HESX1. In addition, direct sequencing of HESX1 was performed in 126 patients with familial hypopituitarism from 66 unrelated families and in 11 patients born to consanguineous parents. All patients studied had at least 1 of the 3 classic features associated with septooptic dysplasia (optic nerve hypoplasia, hypopituitarism, and midline forebrain defects). The overall incidence of coding region mutations within the cohort was less than 1%. McNay et al. (2007) concluded that mutations within HESX1 are a rare cause of septooptic dysplasia and hypopituitarism, and that the large number of familial patients with septooptic dysplasia in whom no mutations were identified is suggestive of an etiological role for other genetic factors.