A new case with Hermansky-Pudlak syndrome type 9, a rare cause of syndromic albinism with severe defect of platelets dense bodies.

Hermansky-Pudlak syndrome (HPS) is a rare form of syndromic oculocutaneous albinism caused by disorders in lysosome-related organelles. Ten genes are associated with different forms of HPS. HPS type 9 (HPS-9) is caused by biallelic variants of BLOC1S6. To date, only three patients with HPS-9 have been reported. We described one patient presenting with ocular features of albinism. Genetic analysis revealed two compound heterozygous variants in the BLOC1S6 gene. Extended hematological studies confirmed the platelet storage pool disease with absence of dense granules and abnormal platelet aggregation. By reviewing the previous published cases we confirm the phenotype of HPS-9 patients. This patient is the only one described with dextrocardia and abnormal psychomotor development.

Higher vitamin D levels in Nigerian albinos compared with pigmented controls.

BACKGROUND: Several studies have suggested that the lower vitamin D levels in blacks is attributable to the effect of increased pigmentation in blocking cutaneous ultraviolet (UV)-mediated production of vitamin D. Albinos are devoid of melanin and should invariably have higher vitamin D levels when compared with their pigmented counterparts. However, strict photoprotection required in their medical management has been shown to reduce UV-dependent vitamin D production. Associations between low vitamin D and several diseases suggest that the pattern of vitamin D in the black African albino be investigated. OBJECTIVE: To compare the vitamin D levels between albinos and normal pigmented controls in Anambra State, Nigeria, and thus highlight the impact of skin pigmentation and sun protection practices on vitamin D levels. METHODOLOGY: This was a cross-sectional study of a consecutive series of albinos from the Albino Foundation, Anambra State. The vitamin D levels of 61 albinos and 58 matched pigmented controls were analyzed. The sun exposures of the participants were calculated using validated sun exposure questionnaires. RESULTS: The albinos had significantly higher vitamin D levels (median 95.9 [50.1-177.4] ng/ml) than the controls (78.2 [12.1-250] ng/ml). None of the albinos had low vitamin D levels. None of the sun protection practices had significant effects on vitamin D levels. CONCLUSION: This study contests the claim that black Africans including albinos have low vitamin D levels. Albinos living in South East Nigeria have significantly higher vitamin D levels than their pigmented counterparts.

Vitamin D levels in patients with albinism compared with those in normally pigmented Black patients attending dermatology clinics in the Free State province, South Africa.

BACKGROUND: Associations between vitamin D deficiency and a broad variety of independent diseases, including several bone diseases, various types of cancer, autoimmune diseases, hypertension, and cardiovascular disease, have been suggested. It is therefore important to detect and treat vitamin D deficiency in high-risk groups. Because patients with albinism (PWA) practice a policy of strict sun avoidance, they may be at risk for low levels of vitamin D. OBJECTIVES: This study was conducted in patients attending dermatology clinics in the Free State, South Africa, to determine sun avoidance behavior in the patient population and to compare 25-hydroxyvitamin D (25[OH]D) levels in PWA with those in normally pigmented Black patients attending the same clinics. METHODS: Serum 25(OH)D levels were assessed in 50 PWA and 50 normally pigmented Black control subjects. Questionnaires on sun exposure avoidance behaviors were administered to all participants. RESULTS: The present study showed no statistically significant difference in median 25(OH)D levels between PWA and controls with normally pigmented Black skin. Rather, the study found a tendency for controls to have lower 25(OH)D levels. A total of 53% (n = 53) of all study participants (PWA and controls) had a 25(OH)D level of <20 ng/ml; thus most participants were deficient in vitamin D. Most of the PWA who participated in the study did not adhere to strict sun avoidance behavior. CONCLUSIONS: People with albinism attending dermatology clinics in the Free State, South Africa, need not be viewed as specifically at risk for low vitamin D levels.

An investigation into a possible relationship between vitamin D, parathyroid hormone, calcium and magnesium in a normally pigmented and an albino rural black population in the Northern Province of South Africa.

Vitamin D levels are important in the management of patients with various disorders of calcium metabolism associated with rickets, osteomalacia, osteodystrophy osteoporosis and hypoparathyroidism. 82 albinos and 58 normally pigmented children resident at the Siloe School for the Visually Impaired were sampled. Blood samples of fasting subjects were collected over a two-day period and analyzed for vitamin D, parathyroid hormone, plasma calcium and both plasma and red blood cell magnesium measurements. The height and weight of each subject was also recorded. The results are discussed in relation to the different skin pigmented groups, for specific age groups, sex and visual status. Statistical outliers were excluded from the results. It appears that the Albino group has significantly (p = 0.06) higher vitamin D levels against the background of a similar dietary intake and similar exposure to sunlight/day length. Thus black children/subjects require a significantly higher intake of vitamin D to attain the same level as their Albino counterparts. In spite of significantly higher vit D levels, the other homeostatic control mechanisms were not altered (i.e., PTH levels are similar in both groups). This study supports the postulate that a dark complexion predisposes to sub-optimal vit D status.

[Thrombocyte dysfunction in children with albinism]. / Thrombocytafunkció-zavar albínó gyermekekben.

Seven children with albinism were examined for haemorrhagic diathesis. In 6 patients coagulation screening tests (prothrombin time, activated partial thromboplastin time, thrombin time) were normal, in 1 patient prolongation of activated partial thromboplastin time due to mild factor XI deficiency was found. Platelet counts were in the reference range, however, the template bleeding time of 6 out of 7 patients was prolonged. Evaluation of platelet aggregation and secretion in a lumi-aggregometer demonstrated that only the child with normal bleeding time had normal platelet function, and 6 children with prolonged bleeding time had impaired aggregation and release reaction. Five out of these 6 patients had severe decrease of ATP secretion even when high dose of thrombin was used as agonist. The number of dens granules in the platelets of these patients, as measured by the uptake of mepacrine, was significantly less than in normal controls. These findings clearly suggested storage pool deficiency. In one of these patients storage pool deficiency was associated with mild factor XI deficiency. The high frequency of haemorrhagic diathesis in albino children emphasizes, the importance of the screening of patients with albinism for bleeding diathesis.

Effects of sex-linked imperfect albinism (sal-s) in the chicken on the relationships of plasma concentrations of progesterone and 17 beta-estradiol with egg production.

Effects of the sal-s gene for sex-linked imperfect albinism on the relationships of plasma concentrations of progesterone (P4) and estradiol (E2) with egg production were investigated during the laying period. Egg production of 17 albino and 16 nonalbino hens was recorded from 19 to 60 wk of age. Blood samples of these hens were taken between 1330 and 1500 h at 19 and 20 wk of age and every 4 wk until 60 wk of age. At 61 wk, blood samples were taken 6, 5, and 4 h before a midsequence ovulation. Plasma P4 and E2 were measured by RIA. There was no difference between genotypes in days to first egg (157.8 vs 158.1 d). Hen-day egg production of albinos was greater (P < 0.05) than that of nonalbinos in the 4-wk periods between 52 and 56 wk (83.8 vs 69.2%) and 56 and 60 wk (81.3 vs 64.3%). Egg production for the entire laying cycle was not different between genotypes (81.0 vs 73.0%, P = 0.08). Plasma P4 and E2 concentrations were not different between albino and nonalbino hens. From 28 to 60 wk of age, partial correlation coefficients between P4 and egg production, and E2 and egg weight were significant for albino hens (r = 0.15 and 0.16, respectively) but not for nonalbinos (r = -0.03 and -0.1, respectively), and age and P4 concentrations were negatively correlated for both albinos (r = -0.22, P < 0.01) and nonalbinos (r = -0.32, P < 0.01). Preovulatory levels of P4 in albino hens were higher (P < 0.05) than those in nonalbinos. Plasma E2 was higher in albinos than in nonalbinos 5 h before ovulation (P < 0.05). These data suggest that increased egg production of albino hens is associated with differences in P4 and E2 metabolism.

Loss of fumarylacetoacetate hydrolase is responsible for the neonatal hepatic dysfunction phenotype of lethal albino mice.

Mice homozygous for the c14CoS albino deletion die as neonates as a result of liver dysfunction. Previous mapping studies have associated this defect with a 310-kb fragment encoding the hepatocyte-specific developmental regulation locus (alf/hsdr-1). The gene encoding fumarylacetoacetate hydrolase (Fah), a metabolic enzyme that catalyzes the last step of tyrosine catabolism, also maps to the same deletion interval. To test whether the neonatal defects found in the albino deletion mutants are attributable to loss of Fah, and not to another gene mapping to the deletion, we have generated Fah mutant mice by gene targeting in embryonic stem cells. Fah-deficient mice die within 12 hr after birth from hypoglycemia and liver dysfunction. In addition, the same pattern of altered liver mRNA expression found in the albino deletion mutants was also found in affected animals. We conclude that the neonatal lethal and liver dysfunction phenotype of the alf/hsdr-1 deletion is entirely attributable to loss of Fah.

Effects of sex-linked imperfect albinism in the chicken (sal-c) on plasma luteinising hormone concentrations and early egg production.

1. When measured before and after the onset of darkness, plasma LH concentrations in 40-day-old sex-linked albino pullets (sal-c) were slightly lower than those of nonalbinos (s+). 2. This finding prompted an experiment in which plasma LH concentrations were measured between 12 and 33 weeks of age when daylength was increased at 15 or 21 weeks. Egg production of the early and late maturing albino hens was measured. 3. Plasma LH concentrations overall and at 17 weeks were lower for albinos than for nonalbinos. In the early maturing group egg production of albinos was higher than that of nonalbinos. 4. Results suggest that increased egg production of albinos is not the direct result differences in plasma LH concentrations but may be a consequence of differences in the control of LH secretion.

Hermansky-Pudlak syndrome: correction of bleeding time by 1-desamino-8D-arginine vasopressin.

The effect of the synthetic vasopressin derivative 1-desamino-8D-arginine vasopressin (DDAVP = desmopressin) on bleeding time was studied in three patients with Hermansky Pudlak syndrome. A good response was observed in this type of storage pool disease. DDAVP might be useful in managing the bleeding disorder found in patients with the Hermansky-Pudlak syndrome.

Reliability of absent platelet dense bodies as a diagnostic criterion for Hermansky-Pudlak syndrome.

The clinical, pigmentary, and ceroid storage manifestations of the Hermansky-Pudlak syndrome (HPS) triad of albinism, hemorrhagic diathesis, and ceroid storage disease are variable. Therefore, a rapid and accurate method of diagnosing HPS is needed. Platelets of 66 albinos were examined by electron microscopy for the presence or absence of dense bodies. Results show that patients reexamined over a period of 1 year had consistent findings. Those lacking dense bodies (15) when first examined also lacked dense bodies when reexamined a year later, and they had evidence of ceroid storage. Those with dense bodies when first examined (8) also had dense bodies when reexamined, did not have evidence of storage disease, and had types of albinism other than HPS. Of 20 propositi lacking dense bodies, all 32 albino relatives also lacked dense bodies, while 6 albino relatives of 6 propositi with dense bodies also had dense bodies in their platelets. The evidence supports the concept that HPS is a distinct genetic and biochemical disease in which the components of the triad are the result of a single genetic defect, either a point mutation or a small deletion. Comparison of whole mount preparations with thin section preparations of 13 albinos shows that whole mount preparations are an accurate and rapid method for diagnosing HPS. The most consistent diagnostic feature of HPS is lack of platelet dense bodies.

Hermansky-Pudlak platelets: further studies on release reaction and protein phosphorylations.

Platelets from a patient with the Hermansky-Pudlak syndrome were studied. These platelets had decreased amounts of serotonin and adenine nucleotides, and a decreased number of mepacrine-labeled dense bodies. beta-Thromboglobulin and acid hydrolases contained in alpha-granules and lysosomes respectively were present in normal amount. Platelets in platelet-rich plasma did not respond to collagen, but arachidonic acid and ionophore A 23187 induced normal aggregation and normal thromboxane (TX) synthesis. Alpha-granule release was found impaired and remained subnormal even with high doses of inducers. In response to thrombin aggregation, release and TX synthesis of isolated metrizamide gradient platelets were found at lower than normal levels. Phosphorylation of P20 and P43 proteins was normal. Only a combination of ADP plus thrombin could restore a normal aggregation, with normal alpha-granule and lysosome release and normal TX synthesis. These results indicated that in the absence of dense bodies: the release of other granules is impaired; the TX synthesis is delayed except when induced by arachidonic acid and A 23187 ionophore; the absence of dense bodies could be compensated for by the addition of ADP which restores the impaired release reaction and TX formation; and P20 and P43 polypeptides were phosphorylated as rapidly as those in normal platelets.

Plasma 5-S-cysteinyldopa concentrations in oculocutaneous albinism.

5-S-cysteinyldopa concentrations were determined by high-pressure liquid chromatography and electrochemical detection in plasma from normally pigmented patients and patients with oculocutaneous albinism, both tyrosinase-positive and tyrosinase-negative. The plasma 5-S-cysteinyldopa concentrations were similar in all three groups, suggesting that 5-S-cysteinyldopa can be produced by mechanisms which do not involve tyrosinase.

[Seroanthropological studies of albino and melanoderm Bamiléké populations (Cameroon). ABO and Rhesus erythrocyte groups, hemoglobin S and taste sensitivity to phenylthiocarbamide]. / Etudes séroanthropologiques des populations albinos et mélanodermes bamilékés (Cameroun). Groupes érythrocytaires ABO et Rhésus, hémoglobine S et sensibilité gustative à la phénylthiocarbamide.

Human oculocutaneous albinism is a recessive autosomic hereditary disease with a prevalence of 1/8,500 in bamileke tribe (Cameroon). ABO and Rhesus red blood cell group repartition, presence of hemoglobin S, taste sensitivity for phenylthiocarbamid in a group of 100 albino bamileke subjects were compared with these of 100 black bamileke subjects. There is no significant difference for these genetic markers mentionned above between albino and black bamileke subjects.

Isolation and purification of ceruloplasmin in oculocutaneous albinism, Menkes' disease, Wilson's disease and pregnant women.

A method is reported for isolation and purification of human ceruloplasmin and apoceruloplasmin from serum. It involves a rapid and mild procedure by ion exchange chromatography on DEAE-Sephacel using a pH and ionic strength concave gradient. It was applied to serum of patients with oculocutaneous albinism, Wilson's disease, Menkes' disease and pregnant women. The ceruloplasmin obtained by this method is undegraded, and homogeneous by physico-chemical and immunochemical analysis.

Copper metabolism study in oculocutaneous albinism.

Abnormal copper metabolism has been described in some pigmentary retinopathies. Albinism is a manifestation of a metabolic disorder in which lack of pigmentation is a prominent feature and changes in the retinal pigment epithelium are found as well. We examined the blood and urine of two groups of patients, albino and control groups, for copper, zinc and ceruloplasmin in serum and copper excretion in urine. We found in the albino group, elevated values of ceruloplasmin which was highly significant when compared to the control group. The mean copper concentration in serum was found to be high as well. The urinary copper was distinctly elevated in four patients of the albino group. Therefore, our results suggest that there might be a primary abnormality of copper metabolism in these patients.

Platelet aggregation independent of ADP release or prostaglandin synthesis in patients with hermansky-Pudlak syndrome.

Platelets from patients with the Hermansky-Pudlak (HPS) syndrome are deficient in the storage pool of adenine nucleotides and serotonin. As a result, the storage pool deficient (SPD) platelets develop only single waves of clumping when stimulated by threshold concentrations of aggregating agents which cause irreversible, biphasic aggregation of normal platelets. Yet, patients with HPS either have no bleeding problems or only mild symptoms. In the present study we have evaluated the importance of prostaglandin synthesis and secretion to the irreversible aggregation of HPS platelets. Results of the study demonstrate that aspirin-treated SPD platelets, which cannot form thromboxane or undergo the release reaction on stimulation by arachidonate, can still undergo irreversible aggregation in response to thrombin and ADP if treated first with epinephrine. A mechanism of membrane modulation mediated by alpha-adrenergic receptors cooperatively linked to the endoperoxide and thromboxane receptor can secure irreversible aggregation of normal or abnormal platelets despite absence of secretion and prostaglandin synthesis.

DOPA in sympathetic nerve tissue--a possible source of serum DOPA in albino animals.

Dopa, catecholamines, and dopac were determined in superior cervical ganglia of albino rats. The average amount of dopa in ganglia of control animals was 1.1--1.6 micrograms/g. The concentrations of catecholamines and dopac were similar to values reported by others. The tyrosine hydroxylase inhibitor alpha-methylparatyrosine methyl ester caused marked decrease in the dopa concentration in the ganglia. The effect of reserpine was less pronounced. The aromatic amino acid decarboxylase inhibitor NSD 1015 markedly increased the dopa concentration.

[Seric ceruloplasmin in melanodermic and albino inhabitants of Cameroon (author's transl)]. / La céruloplasmine sérique chez les sujets mélanodermes et albinos au Cameroun.

The mean value of seric ceruloplasmin in 120 albino inhabitants of Cameroon is 36 +/- 10 mg/ 100 ml. It differs (P < 0,001) much significantly from the value observed (50 +/- 11 mg/100 ml) in a group of 71 registered melanodermic individuals. If compared to the melanodermic reference group, there is a significant increase of the seric ceruloplasmin value, in patients affected by inflammatory lung diseases, and a very significant difference with a group of pregnant women at delivery time.