Haberland Syndrome (Encephalocraniocutaneous Lipomatosis)

The pathogenesis of Haberland syndrome remains unknown. Dysgenesia of the cephalic neural crest and the anterior neural tube is a most widely accepted theory of the pathogenesis of Haberland syndrome. Haberland and Perou speculated as to whether the ectodermal malformations are caused by the same basic defect responsible for the mesenchymal malformations or whether they were secondary to the mesodermal dysgenesis.[1] No evidence exists as yet of genetic transmission or chromosomal abnormality.

Happle and Steijlen suggested that the origin of this nonhereditary genodermatosis could be a lethal autosomal mutation that survives in a mosaic state.[9]

In 2004, Cultrera et al described a female infant that showed significant overlap of encephalocraniocutaneous lipomatosis with oculocerebrocutaneous Delleman syndrome.[10] According to these authors, such overlap may support the theory of somatic mosaicism.

Legius et al reported a unique case of a child having clinical findings of Haberland syndrome and features of neurofibromatosis type 1 (NF-1), in whom a de novo mutation of the NF1 gene was detected; however, because of the relatively high incidence of NF-1 in the general population, a coincidental occurrence of both disorders in the same patient cannot be excluded.[11]

Approximately 60 patients are reported in the literature. No epidemiological data on the frequency of the disorder are available. No clear racial predilection exists.

So far, the syndrome has been found in an almost equal number of girls and boys (5:6). Skin manifestations usually are evident at birth. Seizures may develop at any age and may be responsible for intellectual impairment when appearing in young children.

The prognosis appears to correlate with the progression of neurologic lesions, either directly or secondary to complications from drug and surgical therapies. Many patients with Haberland syndrome lead normal lives. Complications usually are caused by intracerebral malformations.

In a study by Donaire et al, functional MRI revealed transfer of memory and language functions to the nonaffected hemisphere, providing evidence that functional reorganization and restoration of cognitive function may occur in persons with encephalocraniocutaneous lipomatosis.[12]

The clinical picture of Haberland syndrome may vary from patient to patient; however, a set of clinical features is regarded as characteristic for the disorder.[13] The primary clinical features noted for almost all cases are as follows:

• Unilateral porencephalic cysts with cortical atrophy

• Intracranial lipomas, often located in the cerebellopontine angle

• Ipsilateral connective tissue usually lipomatous hamartomas of the scalp, eyelid, and outer globe of the eye (bilateral eye involvement in 1 report)[14]

• Cranial asymmetry

• Marked developmental delay and mental retardation

• Seizures

• Spasticity of the contralateral limbs

• Unilateral odontomas (1 report)[15]

The diagnosis of encephalocraniocutaneous lipomatosis (ECCL) is mainly based on history, clinical examination, and imaging studies. Original diagnostic criteria were published by Hunter in 2006. In 2009 Moog has analyzed 54 patients with encephalocraniocutaneous lipomatosis and proposed revised diagnostic criteria.[16]

Table. Revised Diagnostic Criteria for Encephalocraniocutaneous Lipomatosis ^[16] (Open Table in a new window)

The characteristic cutaneous neoplasm, named nevus psiloliparus (Greek for hairless fatty nevus), has been noted so far only in patients with encephalocraniocutaneous lipomatosis (ECCL).[17] In 2004, Happle and Horster reported nevus psiloliparus in 2 otherwise healthy girls, suggesting that the skin lesion may be a nonsyndromic skin disorder[18] ; however, it still remains a characteristic change for encephalocraniocutaneous lipomatosis. Large, slightly protuberant, soft tissue masses of the scalp are located on one side of the scalp and usually do not cross the midline, but bilateral involvement also has been reported. These cutaneous soft tumors, often lipomas, have overlying skin devoid of hair.

Alopecia is a constant finding.[19]

Cutaneous abnormalities usually involve only the head and face; however, they may be documented soon after birth.[20]

Some patients have ill-defined bony protuberances on the skull (associated with the scalp), subcutaneous lipomatous nodules, and tumors. Note the image below.

A child with Haberland syndrome. Apparent alopecia and small cutaneous soft lipomas on the face and eyelid.

Skin-colored papular or polypoid cutaneous nodules may be observed on the face and eyelid in a unilateral distribution on the same side as the scalp lesions. These may represent small angiolipomas, fibrolipomas, connective tissue nevi, or mixed hamartomas of cartilage, fat, and connective tissue. Mandibular osteomas have also been reported.

Pigmented melanocytic nevi are another skin abnormality found in some patients with encephalocraniocutaneous lipomatosis.

Ocular involvements appear to be a uniform feature of Haberland syndrome. The most common ocular abnormalities include epibulbar choristomas, small papules around the eyelids, and desmoid tumors of the scleral limb. Persistent hyaloid vessels, dislocation of the lens capsule, clouding of the cornea, iris dysplasia, colobomas, microphthalmia, ocular calcifications, and optic nerve pallor also have been reported. Ocular manifestations may be bilateral. Almer et al reported a case of encephalocraniocutaneous lipomatosis with bilateral aniridia.[21] Valladares et al described a patient (a full-term newborn) with bilateral conjunctival tumors.[22]

Neurological manifestations occur to variable degrees. Mental status of the reported cases varies from totally normal to severe mental retardation. Seizures also are not a constant feature and may become evident in some patients in the first year of life, leading to mental retardation (only in adolescence in others). In most patients, testing of intellectual function revealed IQ scores ranging from 65-75. Spasticity, hemiplegia, and facial paresis also have been described in patients with encephalocraniocutaneous lipomatosis. One patient, delineated by Fishman in 1987, developed a subarachnoid hemorrhage, presumably related to leakage of blood from an aneurysmal-type vascular malformation.[23]

Other abnormalities found on physical examination of patients with encephalocraniocutaneous lipomatosis include vertebral abnormalities, extradural spinal cord lipomatous lesions, or leg, arm, or chest asymmetry. Thakur et al present a case of a patient with a large temporal exostosis.[24] Pregowska et al report an infant with multifocal atrial tachycardia.[25]  Moog also found congenital heart malformations in five of 54 analyzed patients, in particular aortic coarctation (4 of 5).[16]

Some authors have recognized similarities in the clinical picture of encephalocraniocutaneous lipomatosis and oculocerebrocutaneous lipomatosis (Delleman syndrome). Hunter compared the clinical picture of both syndromes (40 patients with Delleman syndrome and 44 with encephalocraniocutaneous lipomatosis) but the correlation remains unclear.[26]

Some authors also propose oculoectodermal syndrome as a milder variant of encephalocraniocutaneous lipomatosis, without intracranial lipomatosis.[27]

Perform neuroimaging studies in all patients with encephalocraniocutaneous lipomatosis (ECCL).

Enlargement of the lateral ventricle, the intracranial cysts, atrophy of the cerebral hemisphere ipsilateral to the cutaneous lipomatous hamartomas, and intracranial lipoma were the most common findings on CT scan or MRI of the head.[28, 29] In a comprehensive review of 52 patients from the literature, Moog et al found 33 (64%) who showed intracranial lipomas, frequently of cerebellopontine location.[30] See the image below.

CT scan shows an enlargement of the left lateral ventricle in a child with Haberland syndrome. Note an asymmetry of the hemispheres and calcifications in the midline.

Other alterations, including pontocerebellar atrophy, endocranial hypertension, porencephaly, perimedullary lipomas, and partial agenesis of the corpus callosum, also have been reported. Cortical calcifications and areas of cortical dysplasia have been documented in several patients. It has been proposed that some of those changes may result from focal vascular defects.[16] The serial imaging studies demonstrated the progression of CNS abnormalities.

There are also reports of low-grade gliomas in four patients with encephalocraniocutaneous lipomatosis.[31] In all cases, gliomas were located in the midline, in hypothalamic and suprasellar regions.

Due to the possible presence of extradural spinal cord lipomatous lesions, some authors suggest screening for spinal abnormalities in asymptomatic patients. Spinal lipomas have been documented in 12 of 13 patients who had imaging studies of the spine.[30] They can extend over the whole length of the spinal cord, but most of them remain asymptomatic. Some patients may develop multiple cystic bone lesions.[32]  

A pediatric glioblastoma was described with Haberland syndrome.[33]  

Neurologic symptoms do not appear to be related to the extent of neuroradiologic abnormalities. Most patients had extremely extensive cerebral abnormalities with only minimal symptomatology.

Skin-colored papules predominantly affecting the eyelids, forehead, and cheeks represent fibrolipomas, angiofibromas, papillomas, connective tissue nevi, or hamartomatous tissue consisting of cartilage, fat, and connective tissue. Biopsy specimens taken from the alopecic area of the scalp reveal focal dermal fibrosis associated with increased amounts of subcutaneous fat extending into the upper reticular dermis. The cutaneous and ocular findings are limited to 1 hemicranium and are ipsilateral to the developmental defects of the brain.

The histologic examination of the brain performed in a case reported by Haberland and Perou revealed a defective lamination of the cerebrum, polymicrogyria, and calcification in the outer cerebral cortex overlying the porencephalic cyst.[1]