Phenotypic and microscopic description of a new case of Ermine phenotype.

We describe a new case of Ermine phenotype. The patient had the striking pattern of skin and hair involvement that characterize the condition, global developmental delay, growth retardation, microcephaly, and bilateral hearing loss. Results of extensive workup for several other neurologic, metabolic, mitochondrial, genetic and chromosomal conditions were normal. Microscopic examination demonstrated normal numbers of melanocytes and variable amounts of pigment depending on the degree of pigmentation in the region biopsied. Ultrastructure of melanosomes was abnormal suggesting a defect in melanin synthesis. Ermine phenotype has a distinct clinical presentation compared to other syndromes associated with abnormal pigment and deafness. Therefore, this should be included as an independent condition in the differential diagnosis. Additional phenotypic and pathologic descriptions are needed to better define this condition clinically, pathologically, and genetically.

Uveal melanocytes do not respond to or express receptors for alpha-melanocyte-stimulating hormone.

PURPOSE: Whereas cutaneous pigmentation increases after exposure to ultraviolet (UV) irradiation, ocular pigmentation does not. This study was designed to examine the evidence that alpha-melanocyte-stimulating hormone (alpha-MSH), which is thought to be the mediator of UV response in the skin, has any role to play in uveal melanocytes. METHODS: Human uveal melanocytes derived from the choroid and the iris were cultivated by using eyes harvested from adult cadaveric donors and were assessed by Northern blot analysis for growth and melanogenic response to alpha-MSH and expression of the receptor for alpha-MSH (MC1-R). In addition, expression of alpha-MSH was evaluated in ocular tissue by immunocytochemistry. RESULTS: Uveal melanocytes, unlike cutaneous melanocytes in vitro, exhibited no stimulation of proliferation in response to alpha-MSH at dosages ranging from 0.1 to 100 muM. In addition, tyrosine hydroxylase, DOPA oxidase, and protein levels for tyrosinase, TRP-1, and TRP-2 were not influenced by alpha-MSH. Associated with the lack of alpha-MSH response in cultured uveal melanocytes was the absence of expression of the receptor for alpha-MSH (MC1-R), as assessed by Northern blot analysis. Also in contrast to the skin, pigmented ocular tissue lacked expression of the alpha-MSH ligand, as assessed by immunocytochemistry. CONCLUSIONS: In conclusion, ocular pigmentation does not appear to be regulated by melanocyte stimulating hormone.

Enzyme therapy of gaucher disease: clinical and biochemical changes during production of and tolerization for neutralizing antibodies.

The clinical impact of neutralizing antibodies directed against the therapeutic enzyme was investigated in patients with Gaucher disease. Two patients with Gaucher disease type 1 were followed for their clinical progression during antibody development and clinical changes during tolerization. Patient 1 developed neutralizing antibodies to imiglucerase (GCase) at the 10th month of enzyme therapy. Tolerization was achieved within a 42-month period with a short course of cyclophosphamide and then higher dose enzyme (60 IU/kg/week) alone. Patient 1 continues to improve up to 100 months of enzyme therapy despite the presence of low level in vitro neutralizing antibodies. Patient 2 developed neutralizing antibodies to GCase at the 29th month of enzyme therapy that correlated with clinical deterioration. Clinical stabilization has been observed with increased enzyme therapy (60 IU/kg/week) even in the presence of the neutralizing antibodies. Patient 2 is the first to develop neutralizing antibodies after 12 months of enzyme therapy. Plasma chitotriosidase activities were not well correlated with the clinical course in either patient. The presence of neutralizing antibodies should be suspected in Gaucher disease patients on enzyme therapy who experience diminished response or deterioration. The persistence of minimal amounts of in vitro neutralizing antibodies does not interfere with the therapeutic effectiveness. Chitotriosidase is not a sensitive marker for the severity of disease or disease progression.

Gaucher disease: in vivo evidence for allele dose leading to neuronopathic and nonneuronopathic phenotypes.

Gaucher disease, a common lysosomal storage disorder, is associated with mutations at the acid beta-glucosidase (GCase) locus. Two affected individuals are described to share a common mutant allele, but manifest different clinical categorical phenotypes. A 57-year-old female, with Gaucher disease type 1 and Cherokee ancestry, was homozygous for a rare mutant allele encoding Lys79Asn (K79N). A 2-year-old Caucasian male, with Gaucher disease type 3 and Cherokee ancestry, was a heteroallelic homozygote for this same allele (K79N) and a novel complex mutation (null allele). The shared alleles were identical as determined by complete gene sequencing, suggesting a founder effect. The discrepant phenotypes (types 1 and 3) in these two patients provide support for a threshold of residual activity necessary to "protect" the central nervous system (CNS) from the pathogenic effects of Gaucher disease, indicating an allele dose-effect. Designation of genotype associations with specific phenotypes must be assessed with this perspective.

Upper airway malformation associated with partial trisomy 11q.

11q trisomy is associated with a recognizable pattern of multiple malformations. Review of the literature reveals the following recurrent themes common to complex and isolated 11q trisomy: mental retardation, pre- and postnatal growth retardation, hypotonia, a distinct pattern of facial features, congenital heart defects, and limb malformations. We report four patients with partial trisomy 11q, none of which arose from the common 11/22 translocation. Three of the four patients had the previously unreported finding of upper airway obstruction secondary to a malformed epiglottis. The critical region for this malformation appears to be 11q21-23.2.