Holoprosencephaly-diencephalic hamartoblastoma (HDH).

Holoprosencephaly-diencephalic hamartoblastoma association, Holoprosencephaly-hypothalamic hamartoblastoma, Holoprosencephaly-diencephalic hamartoma

HDH is an extremely rare developmental field defect primarily involving the prosencephalon. The most accredited hypothesis is that the hypothalamic hamartoma formation, which occurs early in embryogenesis, produces a cascading process of subsequent craniofacial defects including holoprosencephaly, microphthalmia, hemifacial microsomia, neuronal migration defects, and brainstem\/posterior fossa and meningeal anomalies.

The inheritance pattern of HDH is still obscure and probably heterogeneous. Environmental\/stochastic causes may also contribute for a significant proportion of cases.

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D054975

672 Pallister-Hall syndrome

C0265220

HDH equally affects males and females. Nearly 100% of the patients present some features of holoprosencephaly. The spectrum of these anomalies is wide, ranging from alobar holoprosencephaly to microforms, such as isolated single central medial incisive, or cleft palate. The most consistent holoprosencephalic features are hypo\/aplasia of the corpus callosum, arhinencephaly and premaxillary agenesis. Unilateral or bilateral microphathalmia and neuronal migration\/cortical anomalies are quite common abnormalities. Additional findings include meningeal abnormalities, such as cysts and dysplasia, and brainstem and posterior fossa malformations. The first and second branchial arches derivatives may also be asymmetrically affected leading to a significant clinical overlap with the oculo-auriculo-vertebral spectrum. Fifty to sixty per cent of the patients also show extracephalic features, with an excess of midline and laterality determination abnormalities, thus configuring a polytopic developmental field defect. The axial skeleton is the most commonly involved structure, while heart, kidneys, gastrointestinal tract, genitourinary system and limbs are more rarely affected.

On embryological perspective, hypothalamic hamartoma\/hamartoblastoma is a malformation, not a true tumor. Other benign growth lesions, including meningeal angiomatosis, frontal lipoma, tongue cyst, epignathus and gum nodules, have been observed in about 20% of the cases. However, no increased risk of malignancies has been reported in HDH patients.

In those patients who survive (see below), the treatment is usually conservative and symptomatic. Surgical repair could be requested for specific potentially life-treating or disfiguring malformations, such as cleft palate, congenital heart disease and genital anomalies. Invasive treatment of hypothalamic hamartomas is usually requested only in presence of intractable seizures. In this case, the experience is limited to non syndromic hamartomas and therapeutic options include surgical resection by conventional craniotomy, microsurgical technique via transcallosal approach and stereotactic radiofrequency thermocoagulation.

HDH usually has a poor prognosis and is lethal in about 50% of the cases. Mental retardation, epilepsy and precocious puberty are quite common complications (50-60%) in the surviving patients.

In one case a 7q36 terminal deletion was demonstrated, while another patient showed a 69, XXX triploid karyotype. Therefore, although rarely positive, standard karyotype and subtelomeric rearrangement analysis are recommended in all HDH patients.

Although mutations of this gene have not yet been identified in HDH, a terminal 7q deletion has been documented in one patient and an additional case, showing single central medial incisive and hypophyseal hamartoma, has been described with SHH heterozygous mutation. These evidences suggest that SHH is a potential candidate-gene for those HDH cases who still lack a known cause (e.g. chromosome imbalance or teratogenic exposure).

A single patient showing a SOX2 heterozygous mutation and presenting with hypothalamic hamartoma, unilateral microphthalmia, hypoplastic anterior hypophysis and corpus callosum has been described. Although the observed phenotype cannot be unambiguously interpreted as an atypical form of holoprosencephaly, future studies are expected to demonstrate a causal relationship between SOX2 mutations and HDH.