Growth Hormone Deficiency: Extending the Phenotypic Spectrum of SALL4-Related Disorders

Background: The SALL4 gene encodes sal-like protein 4, a transcription factor with eight zinc finger motifs that is essential for the development of the epiblast and primitive endoderm. In association with TBX5 (T-box), SALL4 is responsible for the establishment and morphogenesis of the thumb. Pathogenic SALL4 variants have been reported to cause Duane-radial ray syndrome (also known as Okihiro syndrome), acro-renal-ocular syndrome and Holt-Oram syndrome. Hereby, we report on a family with radial hypoplasia and kidney dystopia in members of 4 consecutive generations, and short stature due to growth hormone deficiency (GHD) in the proband. Clinical Case: The male proband was born from the 3rd normal pregnancy at 39th week of gestation. He has no biological siblings. He was born small for gestational age (birth weight 2550 g, length 47 cm - both < 2SD) and had bilateral asymmetrical radial ray malformation consisting of radial hypoplasia, ulnar flexure and bilateral aplasia of the thumb, and pelvic dystopia of his right kidney. He had no cardiac malformations, clubfoot, ocular coloboma or Duane anomaly. He was examined for progressive short stature at the age of 3.9 years, where his IGF-1 was 68 ug/l (-1.0 SD), and peak GH in two stimulation tests was 6.2 ug/l. Other pituitary hormones were normal. His mother’s and father’s heights are 152.3 cm (-2.4 SD), and 177.8 cm (-0.4 SD), respectively. His father has malformation of the forearm that is milder than that of the son. The paternal grandfather is affected as well, with a radial defect with missing opposition of the thumb and height 164 cm (-2.3 SD). The family reports that the phenotype of radial dysplasia was apparent in the paternal grandfather’s mother as well. Due to the suggestive monogenic dominant transmission of the developmental abnormality, we carried out whole exome sequencing that revealed a nonsense variant in the SALL4 gene c.1717C>T (p.Arg573Ter) in the proband, his father, and paternal grandfather. The proband was started with regular GH therapy at age 6.5 years and experienced catch-up growth as expected in GHD. By the age 11 years, his height stabilized at about the 25th percentile in accordance to the mid-parent height with a target height of 171.5 +/- 8.5 cm. Puberty started spontaneously at the age 12.5 years. Conclusion: This is the first case demonstrating a patient with a congenital upper limb defect based on a pathogenic variant of the SALL4 gene where an isolated growth hormone deficiency (GHD) was detected and has been successfully treated with growth hormone. Acknowledgements: Genetic testing was funded by AZV grant NV18-07-00283.

Grandchild’s IQ is associated with grandparental environments prior to the birth of the parents

Background. Despite convincing animal experiments demonstrating the potential for environmental exposures in one generation to have demonstrable effects generations later, there have been few relevant human studies. Those that have been undertaken have demonstrated associations, for example, between exposures such as nutrition and cigarette smoking in the grandparental generation and outcomes in grandchildren. We hypothesised that such transgenerational associations might be associated with the IQ of the grandchild, and that it would be likely that there would be differences in results between the sexes of the grandparents, parents, and children. Method. We used three-generational data from the Avon Longitudinal Study of Parents and Children (ALSPAC). We incorporated environmental factors concerning grandparents (F0) and focussed on three exposures that we hypothesised may have independent transgenerational associations with the IQ of the grandchildren (F2): (i) UK Gross Domestic Product (GDP) at grandparental birth year; (ii) whether grandfather smoked; and (iii) whether the grandmother smoked in the relevant pregnancy. Potential confounders were ages of grandparents when the relevant parent was born, ethnic background, education level and social class of each grandparent. Results. After adjustment, all three target exposures had specific associations with measures of IQ in the grandchild. Paternal grandfather smoking was associated with reduced total IQ at 15 years; maternal grandfather smoking with reduced performance IQ at 8 years and reduced total IQ at 15. Paternal grandmother smoking in pregnancy was associated with reduced performance IQ at 8, especially in grandsons. GDP at grandparents’ birth produced independent associations of reduced IQ with higher GDP; this was particularly true of paternal grandmothers. Conclusions. These results are complex and need to be tested in other datasets. They highlight the need to consider possible transgenerational associations in studying developmental variation in populations.

Biographical Sketches

Chapter 8 presents a partial list of traders, hydrographers, naturalists and others who played a role in Sino-French trade at Canton, and provides brief biographical information about each. A large number had relatives in the colonial or French East India Company administration, or in Canton or other French overseas trading centers. Most came from families that were long established in France, but there were exceptions; the best known include Julien-Joseph Duvelaër and his brother Pierre, whose paternal grandfather immigrated to France from the Netherlands in the seventeenth century; François and Edmond Roth(e), Irish Jacobite refugees who acquired French nationality by naturalization; and the Protestant Charles de Constant, a francophone Swiss whose family fled France during the religious upheavals of the sixteenth century.

A Filipino Child with Cleidocranial Dysplasia and Acute Leukemia: A Case Report

Cleidocranial dysplasia (CCD) is an autosomal dominant skeletal dysplasia whose most common features include late closure of fontanelles, absent or hypoplastic clavicles, and dental abnormalities. This disorder is primarily due to mutations in RUNX2 (CBFA1) gene. Here we present a Filipino child with clinical and radiologic features of CCD who was also diagnosed with B-cell acute lymphoblastic leukemia (ALL). On history, the patient’s father and paternal grandfather also presented with short stature and similar facial features. Association of leukemia and CCD has been noted in the literature. Hence, this report adds to the potential role of RUNX2 gene in leukemogenesis. With the potential predisposition to developing leukemia, this provides implications in genetic counselling and possible recommendations for surveillance later on.

Grandchild’s IQ is associated with grandparental environments prior to the birth of the parents

Background: In spite of convincing animal experiments demonstrating the potential for environmental exposures in one generation to have demonstrable effects generations later, there have been few relevant human studies. Those that have been undertaken have demonstrated associations, for example, between exposures such as nutrition and cigarette smoking in the grandparental generation and outcomes in grandchildren. We hypothesised that such transgenerational associations might be associated with the IQ of the grandchild, and that it would be likely that there would be differences in results between the sexes of the grandparents, parents and children. Methods: We used three-generational data from the Avon Longitudinal Study of Parents and Children (ALSPAC). We incorporated environmental factors concerning grandparents (F0) and focussed on three exposures that we hypothesised may have independent transgenerational associations with the IQ of the grandchildren (F2): (i) UK Gross Domestic Product (GDP) at grandparental birth year; (ii) whether the grandfather smoked; and (iii) whether the grandmother smoked in the relevant pregnancy. Potential confounders were ages of grandparents when the relevant parent was born, ethnic background, education level and social class of each grandparent. Results: After adjustment, all three target exposures had specific associations with measures of IQ in the grandchild. Paternal grandfather smoking was associated with reduced total IQ at 15 years; maternal grandfather smoking with reduced performance IQ at 8 years and reduced total IQ at 15. Paternal grandmother smoking in pregnancy was associated with reduced performance IQ at 8, especially in grandsons. GDP at grandparents’ birth produced independent associations of reduced IQ with higher GDP; this was particularly true of paternal grandmothers. Conclusions: These results are complex and need to be tested in other datasets. They highlight the need to consider possible transgenerational associations in studying developmental variation in populations.

The first case report of polymerase proofreading-associated polyposis in POLD1 variant, c.1433G>A p.S478N, in Japan

Polymerase proofreading-associated polyposis, caused by germline variants in the exonuclease domains of POLD1 and POLE, is a dominantly inherited rare condition characterized by oligo-adenomatous polyposis and increased risk of colorectal cancer, endometrial cancer and brain tumours. We report the first Japanese case of polymerase proofreading-associated polyposis carrying a POLD1 variant. The proband was a Japanese woman who had undergone resections of early colorectal carcinomas repeatedly and a hysterectomy with bilateral oophorectomy for endometrial cancer, all of which were diagnosed within 2 years after the first colectomy at 49 year old. Colonoscopic examinations demonstrated at least 14 non-cancerous polypoid lesions, some of which were histologically confirmed to be adenoma. Multigene panel sequencing identified a missense variant in POLD1 (c.1433G>A). Although her relatives did not undergo genetic testing, her father and paternal grandfather died of brain tumours at 53 and ~30 years of age, respectively.

Two Deaths in the Family: 1526, 1626

Chapters 20–23 are a case study of the family that changed its name over the generations from Brouart to Beroald to Verville. In 1626 the prolific author François Béroalde de Verville died in Tours. He was a medical practitioner and a former cathedral canon. His name and social status had varied throughout his life. One hundred years earlier, in 1526, his paternal grandfather had died some 150 miles away in Saint-Denis, to the north of Paris. Originally from Brussels, he had been a barber-surgeon. Significantly, he had a simpler name, Simon Brouart. Grandson and grandfather never met. Indeed, the one was not born until thirty years after the other died. Their social status differed greatly, and they inhabited vastly different worlds, separated by the advent of humanism, that of the Reformation, and much else. Of the various factors that transformed this family’s social status, the most decisive were learning and literature.