Novel PORCN mutations in focal dermal hypoplasia.

Focal dermal hypoplasia (FDH), Goltz or Goltz-Gorlin syndrome, is an X-linked dominant multisystem disorder characterized primarily by involvement of the skin, skeletal system and eyes. We screened for mutations in the PORCN gene in eight patients of Belgian and Finnish origin with firm clinical suspicion of FDH. First, we performed quantitative PCR (qPCR) analysis to define the copy number at this locus. Next, we sequenced the coding regions and flanking intronic sequences of the PORCN gene. Three de novo mutations were identified in our patients with FDH: a 150-kb deletion removing six genes including PORCN, as defined by qPCR and X-array-CGH, and two heterozygous missense mutations; c.992T>G (p.L331R) in exon 11 and c.1094G>A (p.R365Q) in exon 13 of the gene. Both point mutations changed highly conserved amino acids and were not found in 300 control X chromosomes. The three patients in whom mutations were identified all present with characteristic dermal findings together with limb manifestations, which were not seen in our mutation-negative patients. The clinical characteristics of our patients with PORCN mutations were compared with the previously reported mutation-positive cases. In this report, we summarize the literature on PORCN mutations and associated phenotypes.

Screening of mutations in the PHF8 gene and identification of a novel mutation in a Finnish family with XLMR and cleft lip/cleft palate.

We investigated the prevalence of mutations in the PHD finger protein 8 (PHF8) gene in X-linked mental retardation (XLMR) and facial cleft starting from the original cohort of 7712 patients operated on since 1 January 1950 for cleft lip/cleft palate in the Cleft Centre at the Helsinki University Hospital. From this nationwide material, 18 patients including one family with two male patients with cleft lip/cleft palate and unknown cause of mental retardation (MR) were sequenced for the coding regions and splice sites of the PHF8 gene. A novel missense mutation c.836C>T of the PHF8 gene was identified in a Finnish family with multiple-affected male patients. The mutation resides in exon 8 and changes phenylalanine to serine (F279S) in the functionally important Jmonji C domain of the protein. The clinical phenotype of the male patients was characterized by mild MR, mild dysmorphic features, unilateral cleft lip and cleft palate in one and bilateral cleft lip and cleft palate in the other sibling. The mutation was not present in 200 anonymous blood donors (approximately 300 X-chromosomes). To our knowledge, F279S is the third mutation of the PHF8 gene identified so far.

Further evidence for linkage of autosomal-dominant medullary cystic kidney disease on chromosome 1q21.

BACKGROUND: Autosomal-dominant medullary cystic kidney disease (ADMCKD) is characterized by the development of cysts at the corticomedullary border of the kidneys. It resembles nephronophthisis (NPH) with an autosomal-recessive mode of inheritance. Genetic linkage has been shown either on chromosome 1q21 (ADMCKD1) or 16p12 (ADMCKD2), and families exist who are not linked to the aforementioned loci. No disease-causing gene underlying this disorder has been reported. METHODS: The Finnish Transplantation Register and hospital records were searched to identify all of the ADMCKD families in the Finnish population. Detailed clinical information of the patients was collected. Linkage analysis was used to study whether the Finnish families originating from a homogeneous population showed genetic linkage to the ADMCKD1 or ADMCKD2 loci. Also, the coding region of a strong candidate gene, natriuretic peptide receptor A (NPRA), located on the chromosome 1q21 critical region, was sequenced using polymerase chain reaction sequencing with an ABI 377XL Automated DNA sequencer (Applera Corp., Norwalk, CT, USA). RESULTS: Five of the six families showed linkage to the previously identified region of chromosome 1q21. Family 6 with hyperuricemia as a prominent clinical feature was linked to neither of the ADMCKD loci. Wide interfamiliar and intrafamiliar variability in the clinical picture of the patients was detected. The NPRA gene mutation was excluded as a causative gene by sequencing. CONCLUSION: This study locates the gene for ADMCKD1 close to a marker D1S1595 in a region <5 cM, and further confirms the existence of at least three loci for the medullary cystic kidney disease. Heterogeneity of the symptoms complicates the clinical diagnosis and classification of the patients. Further studies are needed to identify the disease-causing gene.

Nephronophthisis and ulcerative colitis in siblings: a new association.

Nephronophthisis (NPH) is a chronic tubulointerstitial nephritis leading to terminal renal insufficiency. The disease is heterogeneous, but usually the inheritance pattern is autosomal recessive. In 80% of cases, the disease is caused by a homozygous deletion in NPHP1 gene in chromosome 2q13. Ulcerative colitis is an inflammatory bowel disease with chronic diarrhea, rectal bleeding and characteristic histological findings. Its etiology is suggested to be multifactorial, consisting of genetic susceptibility and unknown exogenous factors. We present two siblings with NPH and ulcerative colitis. As NPH in this family is not linked to 2q13, this association may represent a new, syndromic form of NPH.

Evidence for further genetic heterogeneity in nephronophthisis.

BACKGROUND: A new type of nephronophthisis (NPH) has been recently identified in a large Venezuelan kindred: adolescent nephronophthisis (NPH3) causes end-stage renal disease (ESRD) at a median age of 19 years. The responsible gene (NPHP3) maps to 3q21-q22. NPH3 shares with juvenile nephronophthisis (NPH1) the same disease manifestations such as polyuria, polydipsia, and secondary enuresis. Histopathological findings consist of tubular basement membrane changes, cysts at the corticomedullary junction, and a chronic sclerosing tubulointerstitial nephropathy. The only difference is a younger age at ESRD in NPH1 (median age of 13 years) when compared with NPH3. METHODS: In order to evaluate whether there might be a fourth locus of isolated nephronophthisis, we studied eight NPH families without extrarenal disease manifestations and without linkage to the NPH1 locus (NPHP1) on chromosome 2q12-q13. ESRD was reached at ages ranging from 7 to 33 years. Individuals were haplotyped with microsatellites covering the genetic locus of NPHP3. Infantile NPH (NPH2) was excluded in all families by the clinical history and histological findings. RESULTS: In four of the examined families haplotype analysis was compatible with linkage to the NPHP3 locus. In one of these families identity by descent was observed. In contrast, in another four families linkage was excluded for NPHP3. CONCLUSION: Four NPH-families were neither linked to NPHP1 nor to NPHP3, indicating further genetic heterogeneity within the group of nephronophthisis. The finding of further genetic heterogeneity in NPH has important implications for genetic counselling.

Nephronophthisis in Finland: epidemiology and comparison of genetically classified subgroups.

Nephronophthisis--medullary cystic kidney disease is a progressive chronic tubulointerstitial nephritis leading to terminal renal failure. About two thirds of the patients with familial juvenile nephronophthisis, an autosomal recessive disease, have a homozygous deletion at the gene locus on 2q13. Through a nationwide search, 59 patients were ascertained in Finland. The incidence was 1:61,800 live births when calculated over a 20-year period. Of the patients, 17 came from four families showing dominant inheritance and 37 patients from 28 apparently recessive families when classified by family history, clinical features or presence of a deletion on 2q13. Two were considered as new dominant mutations; three sporadic patients could not be classified. The most significant difference between the patients with deletions, patients without deletions but having recessive family history, and patients belonging to families with dominant inheritance was the age at first symptoms, at the start of dialysis and at transplantation. These facts will be of help in determining the mode of inheritance of a sporadic patient without a deletion.

Mutation analysis of LMX1B gene in nail-patella syndrome patients.

Nail-patella syndrome (NPS), a pleiotropic disorder exhibiting autosomal dominant inheritance, has been studied for >100 years. Recent evidence shows that NPS is the result of mutations in the LIM-homeodomain gene LMX1B. To determine whether specific LMX1B mutations are associated with different aspects of the NPS phenotype, we screened a cohort of 41 NPS families for LMX1B mutations. A total of 25 mutations were identified in 37 families. The nature of the mutations supports the hypothesis that NPS is the result of haploinsufficiency for LMX1B. There was no evidence of correlation between aspects of the NPS phenotype and specific mutations.

Molecular studies in Finnish patients with familial juvenile nephronophthisis exclude a founder effect and support a common mutation causing mechanism.

Familial juvenile nephronophthisis (NPH) is an autosomal recessive tubulointerstitial kidney disease associated with formation of medullary and corticomedullary cysts. It progresses to end stage renal failure and its biochemical defect is unknown. An NPH locus has been assigned to a 2 cM interval on chromosome 2q13 by linkage studies. Homozygous deletions of approximately 250 kb have been detected in 80% of familial cases and 65% of sporadic cases and a common mutation mechanism has been suggested. We examined 14 Finnish families for the presence or absence of a deletion. After detecting a deletion in 12 patients belonging to nine families, we studied a possible founder effect by haplotype analysis using markers D2S340, D2S1889, and D2S1893. No common ancestral disease associated haplotype was found suggesting no founder effect. Results of pairwise linkage analyses were suggestive of linkage in the nine families with a deletion (lod scores of 1.39-3.89 at a recombination fraction of 0). Negative lod scores were obtained in the five families without a deletion suggesting that the disease locus in these families lies elsewhere. The end stage renal disease occurred at a more advanced age in patients without a deletion compared to patients with a deletion, indicating a phenotypic difference between these two groups.

Mutation analysis of patients with Hermansky-Pudlak syndrome: a frameshift hot spot in the HPS gene and apparent locus heterogeneity.

Hermansky-Pudlak syndrome (HPS) is a rare, autosomal recessive disorder in which oculocutaneous albinism, bleeding, and lysosomal ceroid storage result from defects of multiple cytoplasmic organelles-melanosomes, platelet-dense granules, and lysosomes. As reported elsewhere, we mapped the human HPS gene to chromosome segment 10q23, positionally cloned the gene, and identified three pathologic mutations of the gene, in patients from Puerto Rico, Japan, and Europe. Here, we describe mutation analysis of 44 unrelated Puerto Rican and 24 unrelated non-Puerto Rican HPS patients. A 16-bp frameshift duplication, the result of an apparent founder effect, is nearly ubiquitous among Puerto Rican patients. A frameshift at codon 322 may be the most frequent HPS mutation in Europeans. We also describe six novel HPS mutations: a 5' splice-junction mutation of IVS5, three frameshifts, a nonsense mutation, and a one-codon in-frame deletion. These mutations define an apparent frameshift hot spot at codons 321-322. Overall, however, we detected mutations in the HPS gene in only about half of non-Puerto Rican patients, and we present evidence that suggests locus heterogeneity for HPS.

Familial juvenile nephronophthisis. An ultrasonographic follow-up of seven patients.

PURPOSE: To evaluate progressive US changes in the kidneys of patients with familial juvenile nephronophthisis (NPH), an autosomal recessive progressive kidney disease with polyuria, polydipsia, anemia and growth retardation. MATERIAL AND METHODS: The data from 29 US investigations of 5 boys and 2 girls comprised findings relating to kidney size, echogenicity of the kidney parenchyma, visualization of the corticomedullary junction, and the parameters of renal cysts. RESULTS: In the early stages of NPH, when the serum creatinine values were between 134 and 370 micromol/l, the corticomedullary differentiation was weak in 6 patients, the echogenicity of the kidney parenchyma was equal to or greater than that of the liver in 5 patients, and 6 patients had developed renal cysts. The findings became more intensive with the progression of NPH. The size of the kidneys remained normal in 4 patients. CONCLUSION: Renal US reveals characteristic changes already in the early stages of NPH and should therefore be an important part of the diagnostics of NPH because no specific diagnostic test is as yet available.

Mechanism underlying early anaemia in children with familial juvenile nephronophthisis.

Familial juvenile nephronophthisis (NPH) is a hereditary form of chronic tubulointerstitial nephritis with onset in childhood. About one-third of patients develop anaemia before renal insufficiency. We investigated the pathogenetic mechanisms leading to anaemia by comparing 6 patients with NPH and 12 reference patients with other renal diseases. We studied their iron metabolism and measured transferrin receptor-ferritin ratios. There was no evidence for iron deficiency or haemolysis. The serum erythropoietin concentrations of the patients with NPH (12 +/- 2.3 U/I) were low compared with the 12 reference patients (25 +/- 18.9 U/I). In the 2 patients with NPH who were fully investigated, the pharmacokinetics of recombinant human erythropoietin appeared normal. Thus, anaemia in patients with NPH does not result from iron deficiency or correlate with impaired iron status. The mechanism underlying the anaemia of NPH appears to affect the function or regulation of the cells producing erythropoietin.

Two more diagnostic signs in the Floating-Harbor syndrome.

A 6-year-old boy with the Floating-Harbor syndrome (F-HS) is described. We propose that his exceptionally high-pitched voice and supernumerary upper incisor are additional diagnostic signs of F-HS. The elevated gliadin antibody levels suggest coeliac disease, which has been described in three out of the 15 previously reported F-HS patients. His facial features and delayed speech development are very characteristic but his shortness (-3 SD) is milder than usual. The patient is a sporadic case like all the F-HS cases so far.

Growth discordancy in twin pregnancies: a risk factor not detected by measurements of biparietal diameter.

Among 460 twin pregnancies delivered at the University Central Hospital of Turku from 1970 to 1981, there were 41 (8.9%) with a weight difference of 25% or more between twins when calculated from the weight of the larger twin. The perinatal death rate in the first group (9.7%) was significantly higher (P less than .01) than the perinatal death rate (3.7%) in the group with the weight difference of less than 25%. The intrauterine mortality rate, in particular, was significantly increased (P less than .001) in the group with 25% or more difference being 6.5-fold when compared with the more difference being 6.5-fold when compared with the group with the lower weight difference. Among 271 twin pregnancies examined by ultrasound one to two weeks before delivery, there were 31 (11.4%) pairs of twins with a 3-mm or more difference in biparietal diameter, 11 (4.1%) with a 4-mm or more difference, and seven (2.6%) with a 5-mm or more difference. The sensitivity of measurements of biparietal diameter to detect the growth discordancy was 9 to 35%, the specificity 90 to 98%, and the positive predictivity 23 to 29%. This study indicates that a divergent growth pattern in twin pregnancy carries an elevated risk of intrauterine death, especially for the smaller twin. Measurement of biparietal diameter is not a method sensitive enough to detect these high-risk twin pregnancies.

Fetal growth and perinatal mortality in twin pregnancy--effect of sick leave and hospitalization.

Fetal growth, birth weight specific mortality rates and effect of sick leave or hospitalization on the fetal growth were investigated in a material of 476 twin pregnancies managed at University Central Hospital of Turku in years 1970-81. Birth weights of twin babies at any gestational age were slightly but not significantly higher than in earlier materials. When compared to growth curve of singleton fetuses, the growth rate of both twins is equal to singletons up to 30th week of pregnancy, being thereafter slower than in singleton pregnancies. Although duration of sick leave and hospitalization increased considerably during the study period, no change in the duration of pregnancy nor in the weight of twin babies occurred. Instead perinatal mortality decreased from 101/per thousand to 36.2/per thousand. Birth weight specific mortality rates did not differ from those in singleton fetuses.