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The phenotypic variability associated with pathogenic variants in Lysine Acetyltransferase 6B (KAT6B, a.k.a. MORF, MYST4) results in several interrelated syndromes including Say‐Barber‐Biesecker‐Young‐Simpson Syndrome and Genitopatellar Syndrome. Here we present 20 new cases representing 10 novel KAT6B variants. These patients exhibit a range of clinical phenotypes including intellectual disability, mobility and language difficulties, craniofacial dysmorphology, and skeletal anomalies. Given the range of features previously described for KAT6B‐related syndromes, we have identified additional phenotypes including concern for keratoconus, sensitivity to light or noise, recurring infections, and fractures in greater numbers than previously reported. We surveyed clinicians to qualitatively assess the ways families engage with genetic counselors upon diagnosis. We found that 56% (10/18) of individuals receive diagnoses before the age of 2 years (median age = 1.96 years), making it challenging to address future complications with limited accessible information and vast phenotypic severity. We used CRISPR to introduce truncating variants into the KAT6B gene in model cell lines and performed chromatin accessibility and transcriptome sequencing to identify key dysregulated pathways. This study expands the clinical spectrum and addresses the challenges to management and genetic counseling for patients with KAT6B‐related disorders., We describe 20 new cases harboring the KAT6B spectrum of disorders, which range from Say‐Barber‐Biesecker‐Young‐Simpson (SBBYSS) to Genitopatellar (GPS) syndrome or an intermediate phenotype. In our holistic approach, we expand the genotypic and phenotypic spectrum of KAT6B spectrum of disorders. Furthermore, we provide extensive clinical phenotyping, explore the impact of genetic counseling for these complex syndromes, and examine molecular mechanisms in RNA‐seq data in an in vitro cell model of truncating KAT6B mutations.

Primary mitochondrial complex I deficiency is the most common defect of the mitochondrial respiratory chain. It is caused by defects in structural components and assembly factors of this large protein complex. Mutations in the assembly factor NDUFAF5 are rare, with only five families reported to date. This study provides clinical, biochemical, molecular and functional data for four unrelated additional families, and three novel pathogenic variants. Three cases presented in infancy with lactic acidosis and classic Leigh syndrome. One patient, however, has a milder phenotype, with symptoms starting at 27 months and a protracted clinical course with improvement and relapsing episodes. She is homozygous for a previously reported mutation, p.Met279Arg and alive at 19 years with mild neurological involvement, normal lactate but abnormal urine organic acids. We found the same mutation in one of our severely affected patients in compound heterozygosity with a novel p.Lys52Thr mutation. Both patients with p.Met279Arg are of Taiwanese descent and had severe hyponatremia. Our third and fourth patients, both Caucasian, shared a common, newly described, missense mutation p.Lys109Asn which we show induces skipping of exon 3. Both Caucasian patients were compound heterozygotes, one with a previously reported Ashkenazi founder mutation while the other was negative for additional exonic variants. Whole genome sequencing followed by RNA studies revealed a novel deep intronic variant at position c.223-907A>C inducing an exonic splice enhancer. Our report adds significant new information to the mutational spectrum of NDUFAF5, further delineating the phenotypic heterogeneity of this mitochondrial defect.

Membrane Protein Palmitoylated 5 (MPP5) is a highly conserved apical complex protein essential for cell polarity, fate and survival. Defects in cell polarity are associated with neurologic disorders including autism and microcephaly. MPP5 is essential for neurogenesis in animal models, but human variants leading to neurologic impairment have not been described. We identified three patients with heterozygous MPP5 de novo variants (DNV) and global developmental delay (GDD) and compared their phenotypes and magnetic resonance imaging (MRI) to ascertain how MPP5 DNV leads to GDD. All three patients with MPP5 DNV experienced GDD with language delay/regression and behavioral changes. MRI ranged from normal to decreased gyral folding and microcephaly. The effects of MPP5 depletion on the developing brain were assessed by creating a heterozygous conditional knock out (het CKO) murine model with central nervous system (CNS)-specific Nestin-Cre drivers. In the het CKO model, Mpp5 depletion led to microcephaly, decreased cerebellar volume and cortical thickness. Het CKO mice had decreased ependymal cells and Mpp5 at the apical surface of cortical ventricular zone compared with wild type. Het CKO mice also failed to maintain progenitor pools essential for neurogenesis. The proportion of cortical cells undergoing apoptotic cell death increased, suggesting that cell death reduces progenitor population and neuron number. Het CKO mice also showed behavioral changes, similar to our patients. To our knowledge, this is the first report to show that variants in MPP5 are associated with GDD, behavioral abnormalities and language regression/delay. Murine modeling shows that neurogenesis is likely altered in these individuals, with cell death and skewed cellular composition playing significant roles.

The human sodium-dependent multivitamin transporter (hSMVT) is a product of the SLC5A6 gene and mediates biotin, pantothenic acid, and lipoate uptake in a variety of cellular systems. We report here the identification of mutations R94X, a premature termination, and R123L, a dysfunctional amino acid change, both in exon 3 of the SLC5A6 gene in a child using whole genome-scanning. At 15 months of age, the child showed failure to thrive, microcephaly and brain changes on MRI, cerebral palsy and developmental delay, variable immunodeficiency, and severe gastro-esophageal reflux requiring a gastrostomy tube/fundoplication, osteoporosis, and pathologic bone fractures. After identification of the SLC5A6 mutations, he responded clinically to supplemental administration of excess biotin, pantothenic acid, and lipoate with improvement in clinical findings. Functionality of the two mutants was examined by 3H-biotin uptake assay following expression of the mutants in human-derived intestinal HuTu-80 and brain U87 cells. The results showed severe impairment in biotin uptake in cells expressing the mutants compared to those expressing wild-type hSMVT. Live cell confocal imaging of cells expressing the mutants showed the R94X mutant to be poorly tolerated and localized in the cytoplasm, while the R123L mutant was predominantly retained in the endoplasmic reticulum. This is the first reporting of mutations in the SLC5A6 gene in man, and suggests that this gene is important for brain development and a wide variety of clinical functions.

Serine biosynthesis defects are autosomal recessive metabolic disorders resulting from the deficiency of any of the three enzymes involved in de novo serine biosynthesis, specifically phosphoglycerate dehydrogenase (PGDH), phosphoserine aminotransferase (PSAT), and phosphoserine phosphatase (PSP). In this study, we performed metabolomic profiling on 4 children with serine biosynthesis defects; 3 with PGDH deficiency and 1 with PSAT deficiency. The evaluations were performed at baseline and with serine and glycine supplementation. Metabolomic profiling performed at baseline showed low phospholipid species, including glycerophosphocholine, glycerophosphoethanolamine, and sphingomyelin. All children had low serine and glycine as expected. Low glycerophosphocholine compounds were found in 4 children, low glycerophosphoethanolamine compounds in 3 children, and low sphingomyelin species in 2 children. Metabolic profiling with serine and glycine supplementation showed normalization of most of the low phospholipid compounds in the 4 children. Phospholipids are the major component of plasma and intracellular membranes, and phosphatidylcholine is the most abundant phospholipid of all mammalian cell types and subcellular organelles. Phosphatidylcholine is of particular importance for the nervous system, where it is essential for neuronal differentiation. The observed low phosphatidylcholine species in children with serine biosynthesis defects that improved after serine supplementation, supports the role of serine as a significant precursor for phosphatidylcholine. The vital role that phosphatidylcholine has during neuronal differentiation and the pronounced neurological manifestations in serine biosynthesis defects suggest that phosphatidylcholine deficiency occurring secondary to serine deficiency may have a significant contribution to the development of the neurological manifestations in individuals with serine biosynthesis defects.

Serine biosynthesis defects can present in a broad phenotypic spectrum ranging from Neu-Laxova syndrome, a lethal disease with multiple congenital anomalies at the severe end, to an infantile disease with severe psychomotor retardation and seizures as an intermediate phenotype, to a childhood disease with intellectual disability at the mild end. In this report we present 6 individuals from 3 families with infantile phosphoglycerate dehydrogenase (PGDH) deficiency who presented with psychomotor delay, growth failure, microcephaly, and spasticity. The phenotype was variable with absence of seizures in 2 sisters in family 1 and 1 infant in family 2 and seizures with pronounced happy affect in 3 sisters in family 3. The initiation of serine treatment had pronounced effect on seizures and spasticity in the sisters in family 3, but minimal developmental effects on the children in families 1 and 2. With such phenotypic variability, the diagnosis of PGDH deficiency can be challenging.

Item does not contain fulltext Developmental and epileptic encephalopathy (DEE) is a group of conditions characterized by the co-occurrence of epilepsy and intellectual disability (ID), typically with developmental plateauing or regression associated with frequent epileptiform activity. The cause of DEE remains unknown in the majority of cases. We performed whole-genome sequencing (WGS) in 197 individuals with unexplained DEE and pharmaco-resistant seizures and in their unaffected parents. We focused our attention on de novo mutations (DNMs) and identified candidate genes containing such variants. We sought to identify additional subjects with DNMs in these genes by performing targeted sequencing in another series of individuals with DEE and by mining various sequencing datasets. We also performed meta-analyses to document enrichment of DNMs in candidate genes by leveraging our WGS dataset with those of several DEE and ID series. By combining these strategies, we were able to provide a causal link between DEE and the following genes: NTRK2, GABRB2, CLTC, DHDDS, NUS1, RAB11A, GABBR2, and SNAP25. Overall, we established a molecular diagnosis in 63/197 (32%) individuals in our WGS series. The main cause of DEE in these individuals was de novo point mutations (53/63 solved cases), followed by inherited mutations (6/63 solved cases) and de novo CNVs (4/63 solved cases). De novo missense variants explained a larger proportion of individuals in our series than in other series that were primarily ascertained because of ID. Moreover, these DNMs were more frequently recurrent than those identified in ID series. These observations indicate that the genetic landscape of DEE might be different from that of ID without epilepsy.

Diagnosis of genetic syndromes may be difficult when specific components of a disorder manifest at a later age. We present a follow up of a previous report [Seeherunvong et al., (2004); AJMGA 127: 149-151], of an individual with 22q duplication and sex-reversal syndrome. The subject's phenotype evolved to include peripheral and central demyelination, Waardenburg syndrome type IV, and Hirschsprung disease (PCWH; MIM 609136). DNA microarray analysis defined the duplication at 22q11.2q13, including SOX10. Sequencing of the coding region of SOX10 did not reveal any mutations. Our data suggest that SOX10 duplication can cause disorders of sex development and PCWH, supporting the hypothesis that SOX10 toxic gain of function rather than dominant negative activity underlies PCWH.

Gain-of-function mutations of NaV1.7 have been shown to produce two distinct disorders: NaV1.7 mutations that enhance activation produce inherited erythromelalgia (IEM), characterized by burning pain in the extremities; NaV1.7 mutations that impair inactivation produce a different, nonoverlapping syndrome, paroxysmal extreme pain disorder (PEPD), characterized by rectal, periocular, and perimandibular pain. Here we report a novel NaV1.7 mutation associated with a mixed clinical phenotype with characteristics of IEM and PEPD, with an alanine 1632 substitution by glutamate (A1632E) in domain IV S4–S5 linker. Patch-clamp analysis shows that A1632E produces changes in channel function seen in both IEM and PEPD mutations: A1632E hyperpolarizes (−7 mV) the voltage dependence of activation, slows deactivation, and enhances ramp responses, as observed in NaV1.7 mutations that produce IEM. A1632E depolarizes (+17mV) the voltage dependence of fast inactivation, slows fast inactivation, and prevents full inactivation, resulting in persistent inward currents similar to PEPD mutations. Using current clamp, we show that A1632E renders dorsal root ganglion (DRG) and trigeminal ganglion neurons hyperexcitable. These results demonstrate a NaV1.7 mutant with biophysical characteristics common to PEPD (impaired fast inactivation) and IEM (hyperpolarized activation, slow deactivation, and enhanced ramp currents) associated with a clinical phenotype with characteristics of both IEM and PEPD and show that this mutation renders DRG and trigeminal ganglion neurons hyperexcitable. These observations indicate that IEM and PEPD mutants are part of a physiological continuum that can produce a continuum of clinical phenotypes.

Purpose: Long QT Syndrome, Marfan Syndrome, hypertrophic and dilated cardiomyopathy are caused by mutations in large, multi-exon genes that are principally expressed in cardiovascular tissues. Genetic testing for these disorders is labor-intensive and expensive. We sought to develop a more rapid, comprehensive, and cost-effective approach. Methods: Paired whole blood samples were collected into tubes with or without an RNA-preserving solution, and harvested for whole blood RNA or leukocyte DNA, respectively. Large overlapping cDNA fragments from KCNQ1 and KCNH2 (Long QT Syndrome), MYBPC3 (hypertrophic and dilated cardiomyopathy), or FBN1 (Marfan Syndrome) were amplified from RNA and directly sequenced. Variants were confirmed in leukocyte DNA. Results: All 4 transcripts were amplified and sequenced from whole blood mRNA. Six known and 2 novel mutations were first identified from RNA of 10 probands, and later confirmed in genomic DNA, at considerable savings in time and cost. In one patient with MFS, RNA sequencing directly identified a splicing mutation. Results from RNA and DNA were concordant for single nucleotide polymorphisms at the same loci. Conclusion: Taking advantage of new whole blood RNA stabilization methods, we have designed a cost-effective, comprehensive method for mutation detection that should significantly facilitate clinical genetic testing in four lethal cardiovascular disorders.

textabstractBackground: Fragile X syndrome (FXS) is caused by loss of function mutations in the FMR1 gene. Trinucleotide CGG-repeat expansions, resulting in FMR1 gene silencing, are the most common mutations observed at this locus. Even though the repeat expansion mutation is a functional null mutation, few conventional mutations have been identified at this locus, largely due to the clinical laboratory focus on the repeat tract. Methodology/Principal Findings: To more thoroughly evaluate the frequency of conventional mutations in FXS-like patients, we used an array-based method to sequence FMR1 in 51 unrelated males exhibiting several features characteristic of FXS but with normal CGG-repeat tracts of FMR1. One patient was identified with a deletion in FMR1, but none of the patients were found to have other conventional mutations. Conclusions/Significance: These data suggest that missense mutations in FMR1 are not a common cause of the FXS phenotype in patients who have normal-length CGG-repeat tracts. However, screening for small deletions of FMR1 may be of clinically utility.

We present a case of 46,XX sex reversal in the absence of SRY but with partial duplication of chromosome 22q. The subject had multiple congenital anomalies but nearly complete masculinization of the external genitalia. Our case along with a previous case supports the existence of a gene on chromosome 22q that can trigger testis determination in the absence of SRY. We proposed that overexpression of the SOX10 gene at 22q13 might be the cause of sex reversal. We investigated 13 additional subjects with SRY-negative 46,XX sex reversal for microduplication of chromosome arm 22q in the region of SOX10 gene, but could not find evidence for it.

X-linked ocular albinism (OA1), Nettleship-Falls type, is characterized by decreased ocular pigmentation, foveal hypoplasia, nystagmus, photodysphoria, and reduced visual acuity. Affected males usually demonstrate melanin macroglobules on skin biopsy. We now report results of deletion and mutation screening of the full-length OA1 gene in 29 unrelated North American and Australian X-linked ocular albinism (OA) probands, including five with additional, nonocular phenotypic abnormalities (Schnur et al. 1994). We detected 13 intragenic gene deletions, including 3 of exon 1, 2 of exon 2, 2 of exon 4, and 6 others, which span exons 2-8. Eight new missense mutations were identified, which cluster within exons 1, 2, 3, and 6 in conserved and/or putative transmembrane domains of the protein. There was also a splice acceptor-site mutation, a nonsense mutation, a single base deletion, and a previously reported 17-bp exon 1 deletion. All patients with nonocular phenotypic abnormalities had detectable mutations. In summary, 26 (approximately 90%) of 29 probands had detectable alterations of OA1, thus confirming that OA1 is the major locus for X-linked OA.

A non-progressive recessive cerebellar ataxia was identified in a highly inbred Cayman island population. Cayman cerebellar ataxia is characterized by marked psychomotor retardation, and prominent cerebellar dysfunction manifested by nystagmus, intention tremor, dysarthric speech, and an ataxic gait. In this study, we identify linkage to chromosome 19p 13.3 using pooled DNA samples of affected individuals from an isolated population as PCR template for a genome wide screen with short tandem repeat markers. Our data demonstrate that the DNA pooling approach to identify disease gene loci is feasible using individuals from isolated populations in which kindred relationships are highly complex and exact relationships between all affected individuals are not known. Genetic fine mapping demonstrates that the genetic disease interval is approximately 9 cM, but contained within a small physical region. The existence of multiple individuals that are recombinant with flanking markers indicates that the disease interval can be further narrowed with additional markers.

Male and female siblings demonstrated similar facial features and had seizures from birth. Neurologic development, which was delayed, began to deteriorate at 1 year. Sudden death occurred at 2 8/12 and 2 3/12 years of age associated with respiratory infections. Tanning of the skin was noted 2 months before death in the first child. In the second child, blood cortisol levels failed to increase after intravenous ACTH administration, and computerized axial tomography (CAT) scans were normal. At autopsy both patients demonstrated adrenal atrophy and degenerative changes of the white matter throughout the neuraxis. We propose that these siblings have a new form of adrenoleukodystrophy that can be distinguished from the X-linked form by onset at birth, clinical appearance, and pattern of inheritance. A comparison of these cases with a second disorder, Zellweger's syndrome, suggests that a distinctive phenotype is associated with intrauterine degeneration of white matter.

Retinoic acid, an analogue of vitamin A, is known to be teratogenic in laboratory animals and has recently been implicated in a few clinical case reports. To study the human teratogenicity of this agent, we investigated 154 human pregnancies with fetal exposure to isotretinoin, a retinoid prescribed for severe recalcitrant cystic acne. The outcomes were 95 elective abortions, 26 infants without major malformations, 12 spontaneous abortions, and 21 malformed infants. A subset of 36 of the 154 pregnancies was observed prospectively. The outcomes in this cohort were 8 spontaneous abortions, 23 normal infants, and 5 malformed infants. Exposure to isotretinoin was associated with an unusually high relative risk for a group of selected major malformations (relative risk = 25.6; 95 per cent confidence interval, 11.4 to 57.5). Among the 21 malformed infants we found a characteristic pattern of malformation involving craniofacial, cardiac, thymic, and central nervous system structures. The malformations included microtia/anotia (15 infants), micrognathia (6), cleft palate (3), conotruncal heart defects and aortic-arch abnormalities (8), thymic defects (7), retinal or optic-nerve abnormalities (4), and central nervous system malformations (18). The pattern of malformation closely resembled that produced in animal studies of retinoid teratogenesis. It is possible that a major mechanism of isotretinoin teratogenesis is a deleterious effect on cephalic neural-crest cell activity that results in the observed craniofacial, cardiac, and thymic malformations.

Salivary Gland Enlargement and Functional Changes During Feeding of Pancreatin to Rats: (Possible Relation to Functional Changes in Cystic Fibrosis)

We have previously described a 14-yr-old boy with hyperuricemia, renal failure, and accelerated purine production resistant in vivo and in vitro to purine analogs. This patient demonstrated normal red cell hypoxanthine-guanine phosphoribosyltransferase (HPRT) heat stability, electrophoresis at high pH, and activity at standard substrate levels. In the present report an abnormal HPRT enzyme was demonstrated by enzyme kinetic study with phosphoribosylpyrophosphate (PRPP) as the variable substrate and inhibitory studies with sodium fluoride. Apparently normal HPRT activity in a patient with hyperuricemia and gout does not exclude a functionally significant HPRT mutation.

Extract: Therapy of identical twin males with the enzyme defect of the Lesch-Nyhan (L-N) syndrome was instituted at 12 hr of age with adenine, 10 mg/kg/24 hr, administered to one twin and folic acid, 15 mg/24 hr, to both. At 4 years of age both twins demonstrate delayed neurologic development and spasticity but are less severely affected than most other patients with this disorder. Administered in subsequent studies to two maternal cousins of the twins who had clinical features of the L-N syndrome and absence of erythrocyte hypoxanthine-guanine phosphoribosyltransferase activity were adenine, 10 mg/kg/24 hr, adenine, 40 mg/kg/24 hr, folic acid, and mono-sodium glutamate. Low dose adenine had a slight suppressive effect on glycine-l-14C incorporation into uric acid; high dose adenine had a strong suppressive effect in the second patient. We conclude that the adenine dose chosen for therapy was too low. 2,8-Dihydroxyadenine, a toxic breakdown product of adenine, was detected in the urine at both adenine dose levels. Folic acid and monosodium glutamate in these patients further stimulate accelerated glycine-l-14C incorporation into uric acid. In vitro transport studies, performed with inverted hamster jejunal preparations, suggest that adenine is largely converted to adenine monophosphate when exposed to the mucosal surface. This may limit the passage of orally administered adenine to the central nervous system in patients. Adenine and purine precursors affect the biochemical pathology of the L-N syndrome, in vivo and in vitro, but therapeutic use of adenine, 10 mg/kg/24 hr, and folic acid started on the 1st day of life did not prevent central nervous system dysfunction. Speculation: Variation in clinical presentation occurs in the Lesch-Nyhan syndrome. Although small therapeutic benefit may be ascribed to folic acid therapy in our patients, this is not established with certainty. A different approach may be required to prevent central nervous system disease in patients treated from birth.

Summary: Factors which may explain lower serum uric acid in a new therapy of patients with glycogen storage disease (GSD) type I have been studied. [1-14C]Glycine incorporation into urine uric acid was 0.68% of the injected dose during a 6-day period of frequent high carbohydrate feedings, 0.40% with the same diet and nocturnal nasogastric feeding by Vivonex, and 0.18% in a control patient with GSD type III. Fractional renal uric acid excretion in the patient with GSD type I increased from 11.3% to 26.3% after beginning nocturnal nasogastric feeding of Vivonex. Red cell phosphoribosylpyrophosphate levels were not changed by the therapy. Addition of Vivonex nocturnal feedings to frequent high carbohydrate feedings (1) decreased the accelerated de novo purine synthesis to a level still higher than control and (2) increased fractional renal uric acid excretion. Speculation: Near normalization of purine metabolism with nocturnal feeding should decrease the risk of gout in GSD type I.

A child with debrancher deficiency presented with myopathy, recurrent hypoglycemia, and growth failure. Evidence for enhanced gluconeogenesis was demonstrated by low postabsorptive gluconeogenic plasma amino acids, a marked fall in alanine during fasting, and a substantial rise in plasma glucose following protein ingestion. The patient was treated with high-protein nocturnal intragastric therapy, which resulted in marked improvement in exercise tolerance, muscle strength and mass, electromyographic findings, and growth.

Cells cultured from the amniotic fluid of a 22-week fetus in a heterozygote for the X-linked Lesch-Nyhan mutation, which results in neurological and developmental disorders, lacked sex chromatin and were unable to incorporate hypoxanthine. The diagnosis of a mutant male was confirmed upon birth of enzyme-deficient, hyperuricemic twin boys whose amniotic membrane cells failed to incorporate hypoxanthine.

Two male half siblings developed rapid progression of neurologic symptoms at 11/2 and 21/2 years of age. Neither boy had a metabolic acidosis. Characteristic features of subacute necrotizing encephalomyelopathy, the neuropathologic basis of Leigh's syndrome, were demonstrated at autopsy. X-linkage of the disorder was considered because the boys had different fathers. An X-linked form of Leigh's syndrome was supported by a review of the literature, which showed an unexplained male/female ratio in Leigh's syndrome of 1.83/1, and a significant excess of male-male siblings. An X-linked form of Leigh's syndrome would explain the excess of males, and may account for some of the clinical and biochemical heterogeneity.

The cerebrohepatorenal (Zellweger) syndrome is a fatal autosomal recessive disorder manifested in the neonatal period by profound hypotonia, psychomotor retardation, dysmorphic features, and an enlarged liver. In this study we demonstrate fivefold or greater increases of very-long-chain fatty acid levels, particularly hexacosanoic acid (C26:0) and hexacosenoic acid (C26:1), in plasma and cultured skin fibroblasts from 20 patients. Similar findings in cultured amniocytes from 3 of 14 women in whom the fetus was at risk of the Zellweger syndrome permitted prenatal diagnosis. Oxidation of very-long-chain fatty acids, which normally takes place in the peroxisome, was impaired in homogenates of cultured skin fibroblasts and amniocytes. This observation extends the evidence that the Zellweger syndrome belongs to the newly formulated category of peroxisomal disorders. The pattern of excess very-long-chain fatty acids differs from that demonstrated previously in patients with childhood adrenoleukodystrophy. The study of very-long-chain fatty acids provides a convenient method for the early diagnosis and prenatal detection of the Zellweger syndrome.

At the eve of its mapping, the pre-molecular picture of the FG syndrome is heavily biased towards the severe end of the phenotypic spectrum because present knowledge is largely based on propositi. It is an X-linked, incompletely recessive, complexly pleiotropic syndrome with considerably variable expressivity. Though a true multiple congenital anomalies/mental retardation (MCA/MR) syndrome, severe malformations are uncommon and involve mostly the anus (60%) and non-colonic GI defects (33%), hypospadias (25%), cleft palate (6%), rarely a congenital heart defect. The complex CNS dysfunctions of congenital hypotonia and all of its sequelae, MR, and occasional seizures, must be attributed to a developmental CNS defect which is rarely demonstrated at pre-mortem, and which is known to involve agenesis of the corpus callosum in some 25% of appropriately studied patients (mostly propositi). Thus, the diagnosis is largely made on a specific constellation of minor anomalies and mild malformations in a hypotonic boy with severe constipation and a very characteristic facial appearance and behavioral phenotype. In about 1/3 of cases, carrier manifestations may be detected physically. New hemizygote manifestations seen in this review of 5 new patients include abnormal eruption of teeth, diastasis between upper central incisors, apparent gynecomastia, cleft lip, and nasolacrimal and helicine fistulae. Only a half hundred or so FG syndrome patients are known, but we suspect the syndrome is much more common than realized, and because of the unfortunate recurrence risk potential, deserves careful consideration in every appropriate case. RFLP mapping studies are urged in order to aid diagnosis of "mild" cases, and prenatal and carrier detection.

We report on six infants with a neonatally lethal malformation syndrome of hypothalamic hamartoblastoma, postaxial polydactyly, and imperforate anus. Some, but not all, patients had laryngeal cleft, abnormal lung lobulation, renal agenesis and/or renal dysplasia, short 4th metacarpals, nail dysplasia, multiple buccal frenula, hypoadrenalism, microphallus, congential heart defect, and intrauterine growth retardation. The infants also had hypopituitarism and hypoadrenalism. All were sporadic cases, parents were not consanguineous, chromosomes were apparently normal. Family histories were unremarkable. There was insecticide and/or herbicide exposure in several of the cases, but no exposures were common to all 6 mothers. Five of the patients were born within an 8-month period, but all in different geographic locations. It is postulated that this is a previously apparently unreported syndrome of presently unknown cause.

A young man is described with overproduction of uric acid and several features of the Lesch-Nyhan (L-N) syndrome, including borderline normal intelligence, mild spasticity and an episode of self-mutilation. Enzymatic analyses of the activity of hypoxanthine-guanine phosphoribosyltransferase (H-G PRT), the defective enzyme in the L-N syndrome, in red cells and fibroblasts from the patient gave normal results, as did studies of heat stability and starch gel electrophoresis of this enzyme from red cell hemolysates. Red cell adenine phosphoribosyltransferase (A-PRT) activity in the patient was increased, as in patients with the L-N syndrome. Several features of purine metabolism in fibroblasts were similar to those in cell lines with H-G PRT deficiency. Both cell lines showed growth resistance to 8-azaguanine compared to cell lines from normal subjects. When the accelerated purine synthesis was measured by formate-1-C 14 incorporation into formylglycinamide ribonucleotide (FGAR) during azaserine block, both cell lines showed further stimulation of purine synthesis by hypoxanthine, whereas control cell lines showed expected feedback inhibition. Fibroblasts from the patient were more sensitive to inhibition of de novo purine synthesis by adenine than those from a normal control subject in a manner previously shown for H-G PRT deficient cell lines. A distinguishing feature was that fibroblasts from patients with H-G PRT deficiency could not grow in culture media with the folic acid antagonist aminopterin, whereas cell lines from the patient and normal control subjects could use hypoxanthine from the media for growth. We suggest that accelerated purine synthesis and clinical and biochemical similarities to the L-N syndrome, but apparently normal H-G PRT activity, constitute a distinct form of primary gout.

A Sodium Transport Inhibitory Factor in the Saliva of Patients with Cystic Fibrosis of the Pancreas

IN recent years several reports1–3 have called attention to a disorder occurring in the paediatric age group which is characterized by marked over-production of uric acid. The clinical features include haematuria and uric acid stone disease, and often, but not always, mental retardation, neurological signs, and self-mutilation. Intravenous injection of glycine-14C into such patients results in a rapid incorporation1 of isotope into urinary uric acid, signifying the presence of a shunt pathway whereby precursor is incorporated into uric acid without previous incorporation into nucleic acid purines.