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Pablo Lapunzina

Publications and source records attributed to Pablo Lapunzina.

At least 19 recordsLinked to original sources
PubMed2026

Androgens mediate sexual dimorphism in Pilarowski-Bjornsson syndrome.

Sex-specific penetrance in autosomal-dominant Mendelian conditions is largely understudied. The neurodevelopmental disorder Pilarowski-Bjornsson syndrome (PILBOS) was initially described in females. Here, we describe the clinical and genetic characteristics of the largest PILBOS cohort to date, showing that both sexes can exhibit PILBOS features, although males are overrepresented. A mouse model carrying a human-derived Chd1 missense variant (Chd1R616Q/+) displays female-restricted phenotypes, including growth deficiency, anxiety, and hypotonia. Orchiectomy unmasks a growth-deficiency phenotype in male Chd1R616Q/+ mice, while testosterone rescues the phenotype in females, implicating androgens in phenotype modulation. In the gnomAD and UK Biobank databases, rare missense variants in CHD1 are overrepresented in males, supporting a male-protective effect. We identify 33 additional highly constrained autosomal genes with missense variant overrepresentation in males. Our results support androgen-regulated sexual dimorphism in PILBOS and open avenues toward understanding the mechanistic basis of sexual dimorphism in other autosomal Mendelian disorders.

Male↗
PubMed2025

Androgens mediate sexual dimorphism in Pilarowski-Bjornsson Syndrome.

Sex-specific penetrance in autosomal dominant Mendelian conditions is largely understudied. The neurodevelopmental disorder Pilarowski-Bjornsson syndrome (PILBOS) was initially described in females. Here, we describe the clinical and genetic characteristics of the largest PILBOS cohort to date, showing that both sexes can exhibit PILBOS features, although males are overrepresented. A mouse model carrying a human-derived Chd1 missense variant (Chd1 R616Q/+) displays female-restricted phenotypes, including growth deficiency, anxiety and hypotonia. Orchiectomy unmasks a growth deficiency phenotype in male Chd1 R616Q/+ mice, while testosterone rescues the phenotype in females, implicating androgens in phenotype modulation. In the gnomAD and UK Biobank databases, rare missense variants in CHD1 are overrepresented in males, supporting a male protective effect. We identify 33 additional highly constrained autosomal genes with missense variant overrepresentation in males. Our results support androgen-regulated sexual dimorphism in PILBOS and open novel avenues to understand the mechanistic basis of sexual dimorphism in other autosomal Mendelian disorders.

CHD1↗
PubMed2006

HRAS mutation analysis in Costello syndrome: genotype and phenotype correlation.

Costello syndrome is a rare condition comprising mental retardation, distinctive facial appearance, cardiovascular abnormalities (typically pulmonic stenosis, hypertrophic cardiomyopathy, and/or atrial tachycardia), tumor predisposition, and skin and musculoskeletal abnormalities. Recently mutations in HRAS were identified in 12 Japanese and Italian patients with clinical information available on 7 of the Japanese patients. To expand the molecular delineation of Costello syndrome, we performed mutation analysis in 34 North American and 6 European (total 40) patients with Costello syndrome, and detected missense mutations in HRAS in 33 (82.5%) patients. All mutations affected either codon 12 or 13 of the protein product, with G12S occurring in 30 (90.9%) patients of the mutation-positive cases. In two patients, we found a mutation resulting in an alanine substitution in position 12 (G12A), and in one patient, we detected a novel mutation (G13C). Five different HRAS mutations have now been reported in Costello syndrome, however genotype-phenotype correlation remains incomplete.

Abnormalities, Multiple↗
PubMed2006

PAR1 deletions downstream of SHOX are the most frequent defect in a Spanish cohort of Léri-Weill dyschondrosteosis (LWD) probands.

Léri-Weill dyschondrosteosis (LWD) is a skeletal dysplasia characterized by disproportionate short stature and Madelung deformity. Mutations or deletions of the SHOX gene have been previously identified as the main cause of LWD. We recently identified the existence of a second class of pseudoautosomal region 1 (PAR1) deletions which do not include SHOX, implicated in the etiopathogenesis of LWD. The deletions map at least 30-250 kb downstream of SHOX, are variable in size and clearly cosegregate with the LWD phenotype. In order to determine the frequency of this new type of deletions in the Spanish population we analyzed the distribution of PAR1 defects, including the screening of SHOX deletions, mutations, and PAR1 deletions downstream of SHOX, in a total of 26 LWD probands by a combination of MLPA, microsatellite analysis, SNP genotyping, dHPLC, and DNA sequencing. A molecular defect was identified in 16/26 LWD patients (61.5%): 10 PAR1 deletions downstream of SHOX, four SHOX encompassing deletions, and two SHOX mutations. No apparent phenotypic differences were observed between patients with SHOX defects and those with PAR1 deletions downstream of SHOX. In the examined cohort of Spanish LWD probands, PAR1 deletions downstream of SHOX represent the highest proportion of identified mutations (38%) compared to SHOX deletions (15%) and mutations (8%). As a consequence of our findings, the screening of this region should be included in the routine genetic testing of LWD. Also, LWD patients who tested negative for SHOX defects should be re-evaluated for PAR1 deletions downstream of SHOX.

Adolescent↗
PubMed2006

Molecular diagnosis of Beckwith-Wiedemann syndrome using quantitative methylation-sensitive polymerase chain reaction.

PURPOSE: Beckwith-Wiedemann Syndrome is caused by defects in imprinted gene expression at 11p15. Currently, quantitative Southern analysis using DNA methylation-sensitive restriction enzymes is used in molecular diagnosis of this syndrome. METHODS: We describe a rapid and highly quantitative test for assessing DNA methylation at 11p15 using sodium bisulfite treatment of genomic DNA coupled with quantitative TaqMan methylation-sensitive polymerase chain reaction. RESULTS: TaqMan MSP can assess DNA methylation at both differentially methylated region (DMR)1 and DMR2 at 11p15. In addition, by using TaqMan MSP we were able to determine the parent of origin of a duplication of 11p15 by quantification of both DMR1 and DMR2 DNA methylation. CONCLUSION: TaqMan MSP method is a robust and rapid method for detecting changes in DNA methylation that compares favorably to the current standard of Southern blot for DNA methylation analysis. Assessment of DMR1 and DMR2 provides the most comprehensive assay for methylation defects in Beckwith Wiedemann Syndrome, accounting for more than 70% of the cases. The advantages of TaqMan MSP are that it requires less DNA and that it is rapid, less labor-intensive, and amenable to high-throughput analysis. Moreover, this approach can be modified to assess DNA methylation changes anywhere in the genome.

Beckwith-Wiedemann Syndrome↗
PubMed2006

Mietens-Weber syndrome: two new patients and a review.

In 1966, Mietens and Weber reported four out of six siblings from a consanguineous couple with growth failure, dislocation of the head of the radii, bilateral flexion contracture of the elbows, short ulnae and radii, bilateral corneal opacities, horizontal and rotational nystagmus, strabismus, small, pointed nose and mild to moderate mental retardation. Since then, only three other cases have been reported. We report on two new cases, a pair of female twins aged 9 years. The patients were born after an uneventful, normal pregnancy, to young and non-consanguineous parents. After birth, physical findings included horizontal nystagmus and dislocation of both elbows because of abnormally short radii and ulnae in both twins. Further clinical examinations showed moderate psychomotor delay with marked language compromise. Karyotypes were normal in both girls. A review of the literature reveals that the Mietens-Weber syndrome is an uncommon disorder with a probable autosomal recessive pattern of inheritance. To our best knowledge, including the two cases reported here, only nine cases have been observed so far. The finding of congenital nystagmus and radii dislocation in a patient with mental retardation is probably nonrandom and is highly suggestive of Mietens-Weber syndrome.

Abnormalities, Multiple↗
PubMed2005

Clinical and molecular studies on two further families with Simpson-Golabi-Behmel syndrome.

The Simpson-Golabi-Behmel syndrome (SGBS) (OMIM 312870) is an overgrowth/multiple congenital anomalies syndrome caused by a semi-dominant X-linked gene encoding glypican 3 (GPC3). It shows great clinical variability, ranging from mild forms in carrier females to lethal forms with failure to thrive in males. The most consistent findings in SGBS are pre- and postnatal macrosomia, characteristic facial anomalies and abnormalities affecting the internal organs, skeleton, and on some occasions, mental retardation of variable degree. SGBS is also associated with an increased risk of developing embryonal tumors, mostly Wilms and liver tumors. We describe two molecularly-confirmed families with SGBS. All patients had typical manifestations of SGBS including some female relatives who had minor manifestations of the disorder. Some patients had novel findings such as a deep V-shaped sella turcica and six lumbar vertebrae. Molecular studies in affected patients showed a deletion of exon 6 in family 1 and an intronic mutation in family 2.

Abnormalities, Multiple↗
PubMed2005

Risk of tumorigenesis in overgrowth syndromes: a comprehensive review.

Overgrowth syndromes (OGS) comprise a heterogeneous group of disorders in which the main characteristic is that either weight, height, or head circumference is 2-3 standard deviations (SD) above the mean for sex and age. A striking feature of OGS is the risk of neoplasms. Here, the relative frequency of specific tumors in each OGS, topographic location, and age of appearance is determined by reviewing published cases. In some OGS (Perlman, Beckwith-Wiedemann, and Simpson-Golabi-Behmel syndromes and hemihyperplasia) more than 94% of tumors appeared in the abdomen usually before 10 years of age, mainly embryonal in type. In Perlman syndrome, only Wilms tumor has been recorded, whereas in Sotos syndrome, lympho-hematologic tumors are most frequent. Based on literature review, a specific schedule protocol for tumor screening is suggested for each OGS. A schedule with different intervals and specific tests is proposed for a more rational cost/benefit program for these disorders.

Abnormalities, Multiple↗
PubMed2005

Higher frequency of uncommon 1.5-2 Mb deletions found in familial cases of 22q11.2 deletion syndrome.

Familial 22q11.2 deletions have been reported as a 6%-28% of the total affected cases of 22q11.2 microdeletion syndrome (del22q11.2). Different deletion genotypes have been described for this disorder, with a predominant 3 Mb deletion present in 90% of the cases, a less common 1.5-2 Mb deletion in 8%, and atypical smaller deletions in 2%. We have studied 15 cases of del22q11.2 from 6 families (two of them three-generation families) that were previously diagnosed through FISH. We have sized the deleted region by allele genotyping of 12-16 polymorphic markers in all cases, and we have found three families affected with the 1.5-2 Mb deletion, two affected with the 3 Mb deletion, and one in which the deletion size could not be determined. This predominance of the smaller 1.5-2 Mb deletions in our familial cases differs from the minor frequency observed in sporadic cases of del22q11.2. This finding suggests that small deletions are more linked to familial inheritance than large ones, possibly due to psychosocial or biological factors associated with differences in the phenotype. Deletion sizing on routine diagnosis may help characterizing the inheritability of 22q11.2 microdeletion syndrome.

Abnormalities, Multiple↗
PubMed2005

Familial occurrence of the IMAGe association: additional clinical variants and a proposed mode of inheritance.

The IMAGe (intrauterine growth retardation, metaphyseal dysplasia, adrenal hypoplasia congenita, genital anomalies) association (online inheritance in man 300290) is a recently reported disorder comprising intrauterine growth retardation (IUGR), metaphyseal dysplasia, adrenal hypoplasia, and genital anomalies. Four children (three males, one female) from a large pedigree (five generations) were studied. Additional members (n = 10), who died during the neonatal period, were born with IUGR and/or hyperpigmentation and are presumed to have been affected, too. All patients in this series were diagnosed during the newborn period. Minimal clinical features and laboratory findings differ with previously reported patients, suggesting variants in their clinical expression. Adrenal insufficiency was variable within patients. All had severe IUGR and marked postnatal growth failure. Sequence analysis of DNA using an automated cycle from two patients revealed no mutation in the dosage-sensitive sex reversal-adrenal hypoplasia congenita critical region on the X chromosome, gene 1. Analysis of the pedigree showed that the disease is inherited via the maternal line, even in the dead children with suspicion of the disease. Hence, the pattern of inheritance in this family of this unusual disorder might be explained in terms of the genomic imprinting hypothesis with expression through maternal transmission involving an autosomal gene. This transmission may have considerable implications for genetic counseling. Furthermore, pediatric endocrinologists must be aware of the possible occurrence of this life-threatening condition in the offspring of nonaffected women when related to a family member with the association of IUGR, metaphyseal dysplasia, adrenal hypoplasia congenita, genital anomalies.

Adrenal Insufficiency↗
PubMed2005

Beckwith-Wiedemann syndrome due to 11p15.5 paternal duplication associated with Klinefelter syndrome and a "de novo" pericentric inversion of chromosome Y.

We report on an infant who had been prenatally diagnosed with Klinefelter syndrome associated with a "de novo" pericentric inversion of the Y chromosome. A re-evaluation at 3 years of age suggested that he was also affected by Beckwith-Wiedemann syndrome (BWS). Karyotype was repeated and fluorescence in situ hybridisation (FISH) analysis revealed trisomy for 11p15.5-->11pter and a distal monosomy 18q (18q23-->qter). Parental cytogenetic studies showed that the father carried a balanced cryptic translocation between chromosomes 11p and 18q. Furthermore, the child had an extra X chromosome and a "de novo" structural abnormality of chromosome Y. Thus, his karyotype was 47,XX, inv (Y) (p11.2 q11.23), der(18) t (11;18) (p15.5;q23) pat. ish der(18) (D11S2071+, D18S1390-). Two markers on the X chromosome showed that the extra X of the child was paternally inherited. No deletions were observed on the structurally abnormal Y chromosome from any of the microsatellites studied. Clinical findings of patients with BWS due to partial trisomy 11p reveal that there is a distinct pattern of dysmorphic features associated with an increased incidence of mental retardation when comparing patients with normal chromosomes. This fact reinforces that FISH study have to be performed in all BWS patients, specially in those with mental retardation since small rearrangements cannot be detected by conventional cytogenetic techniques.

Aneuploidy↗
PubMed2005

Craniofacial dyssynostosis: description of the first four Spanish cases and review.

Craniofacial dyssynostosis (CD) is characterized by premature fusion of the lambdoid and posterior part of the sagittal sutures, and short stature. Thus, the skull shape becomes dolichocephalic with protuberant forehead and either bulging or flat occiput. Facial changes are secondary to the skull defects, and some additional findings have also been described. We report on the first four known Spanish patients. They were unrelated and had Spanish ancestors. In the three previous reports about this syndrome, the authors hypothesized that the frequency of the gene causing CD must be rather high in the Spanish population, and relatively common in areas with Spanish ancestry. We have estimated the minimal birth prevalence of the syndrome in 0.51 per million livebirths. It has been previously suggested that the syndrome is inherited as an autosomal recessive trait, since there were two affected sisters among the nine published cases. Phenotypic variability is discussed in detail in this paper. We also underline several aspects for the anticipatory guidance of affected individuals, especially recommending a neurologic evaluation taking into account the radiologic findings in order to plan early interventions to avoid undesirable consequences of craniosynostosis. It is also recommended to perform additional studies (ophthalmologic, cardiologic, among others) to rule out the existence of associated anomalies, which are more frequent than previously considered.

Child, Preschool↗
PubMed2005

A novel insertion in the FGFR2 gene in a patient with Crouzon phenotype and sacrococcygeal tail.

BACKGROUND: Mutations in the FGFR2 gene are present in several syndromes with craniosynostosis, such as Pfeiffer's, Apert's, and Crouzon's. CASE: We report a case of craniosynostosis (Crouzon phenotype) with tracheal anomalies and a sacrococcygeal tail. In addition, the patient shows dolichoplagiocephaly, prominent occiput, proptosis, mild facial asymmetry, strabismus, small umbilical hernia, and syndactyly of the second and third toes. CONCLUSIONS: Molecular analysis of the FGFR2 gene in this patient revealed a 12-bp insertion (GAGGAGACCTAG) at nucleotide 824. This is an in-frame mutation that adds four amino acid residues to the immunoglobulin IIIa (IgIIIa) domain of the putative protein. This is the first report of an in-frame insertion in exon 8 of FGFR2 in a child with Crouzon's syndrome, tracheal anomalies, and a tail.

Base Sequence↗
PubMed2005

Follow-up and risk of tumors in overgrowth syndromes.

A striking feature of the overgrowth syndromes (OGS) is the risk of cancer. In some OGS (Beckwith-Wiedemann, Perlman, Simpson-Golabi-Behmel syndromes and hemihypertrophy) tumors appeared mostly in the abdomen (more than 94% of tumors), are usually diagnosed before 10 years, and most of them are embryonal. Conversely, in other OGS, such as Sotos syndrome, the most frequent type is lympho-hematological tumors, about two-thirds are extra-abdominal and some of these tumors may appear after the second decade of life. Based on a previous literature review, a specific schedule protocol for tumor screening was suggested for many OGS. In this article we briefly review some aspects of the current knowledge of OGS and tumors, emphasizing the follow-up of these disorders.

Abdominal Neoplasms↗
PubMed2004

Macrocephaly-cutis marmorata telangiectatica congenita: report of six new patients and a review.

We report on six additional patients with macrocephaly-cutis marmorata telangiectatica congenita (M-CMTC; MIM 602501) and review the literature. This syndrome is a multiple congenital anomalies/mental retardation and overgrowth disorder comprising macrocephaly, cutis marmorata, vascular marks of lip and/or philtrum, syndactyly, hemihypertrophy, CNS anomalies, and developmental delay. Based on the findings in our 6 patients and on 69 patients previously reported we listed the very frequent (observed in >75%), frequent (25-75%), and less frequent (>25%) components of the syndrome.

Abnormalities, Multiple↗