Jan M Wit

• MD, PhD
• Professor Emeritus at Leiden University Medical Center

Beckwith–Wiedemann spectrum (BWSp) is an overgrowth disorder caused by (epi)genetic alterations in chromosome 11p15. This study aimed to develop BWSp‐specific growth charts and explore genotype/phenotype correlations with respect to growth. Heights, weights, and head circumferences were retrospectively collected from 581 individuals with BWSp from...

Context The growth hormone (GH) secretagogue receptor, encoded by GHSR, is expressed on somatotrophs of the pituitary gland. Stimulation with its ligand ghrelin, as well as its constitutive activity, enhances GH secretion. Studies in knockout mice suggest that heterozygous loss-of-function of GHSR is associated with decreased GH response to fasting...

Disclosure: J. Vliegenthart: None. J. Wit: None. B. Bakker: None. A. Boot: None. C. de Bruin: None. M. Finken: None. J.V. Heyden: None. M. Houdijk: None. H. van der Kamp: None. E. Van Mil: None. A. Reedijk: None. T. Sas: None. D.A. Schott: None. P. van Setten: None. S. Straetemans: None. V. van Tellingen: None. B. Touwslager: None. A.V. Trotsenburg...

Disclosure: J. Vliegenthart: None. J. Wit: None. B. Bakker: None. A. Boot: None. C. de Bruin: None. M. Finken: None. J.V. Heyden: None. M. Houdijk: None. H. van der Kamp: None. E. Van Mil: None. A. Reedijk: None. T. Sas: None. D.A. Schott: None. P. van Setten: None. S. Straetemans: None. V. van Tellingen: None. B. Touwslager: None. A.V. Trotsenburg...

Introduction: The clinical features of bi-allelic IGF1 defects are well established, i.e., severe growth failure and microcephaly, delayed psychomotor development, and sensorineural deafness. However, information on clinical and endocrine consequences of heterozygous IGF1 variants and treatment options is scarce. We aimed at extending the knowledg...

Introduction: The diagnostic yield of genetic analysis in the evaluation of children with short stature depends on associated clinical characteristics, but the additional effect of parental consanguinity has not been well documented. Methods: This observational case series of 42 short children from 34 consanguineous families was collected by six...

Very tall people attract much attention and represent a clinically and genetically heterogenous group of individuals. Identifying the genetic etiology can provide important insights into the molecular mechanisms regulating linear growth. We studied a three-generation pedigree with five isolated (non-syndromic) tall members and one individual with n...

Current clinical guidelines provide information about the diagnostic work-up of children with growth failure. This mini-review focuses on the nutritional assessment, which has received relatively little attention in such guidelines. The past medical history, in particular a low birth size, early feeding problems and failure to thrive, can provide i...

Idiopathic short stature (ISS) is a diagnosis of exclusion, and therefore each child with short stature or slow growth referred to a paediatrician deserves a full medical history and physical examination, as well as radiological and laboratory screening tests. In patients with an increased likelihood of a genetic cause, genetic testing is indicated...

To optimize care for children with Marfan syndrome (MFS) in the Netherlands, Dutch MFS growth charts were constructed. Additionally, we aimed to investigate the effect of FBN1 variant type (haploinsufficiency [HI]/dominant negative [DN]) on growth, and compare MFS‐related height increase across populations. Height and weight data of individuals wit...

STAT5B deficiency, a rare autosomal recessive disorder characterized by severe growth hormone insensitivity (GHI) and immunodeficiency, can manifest as fatal pulmonary complications. We describe atypical STAT5B deficiency associated with a novel homozygous frame-shift STAT5B variant [c.1453delG, p.(Asp485Thrfs*29)] identified in a young 17.6 yr old...

Context Prediction of adult height (AH) is important in clinical management of short children. The conventional methods of Bayley-Pinneau (BP) or Roche-Wainer-Thissen (RWT) have limitations. Objective To develop a set of algorithms for AH prediction in patients with idiopathic short stature (ISS) which are specific for combinations of predicting v...

IGSF1 deficiency is a rare X-linked condition characterized by central hypothyroidism (CeH) and a wide variety of other clinical features with variable prevalence, including a delayed pubertal testosterone rise and growth spurt in contrast to normal or accelerated testicular growth, and adult macroorchidism with relatively low serum testosterone co...

Objective: To describe clinical, laboratory and genetic characteristics of three unrelated cases from Chile, Portugal and Saudi Arabia with severe insulin resistance, SOFT syndrome, and bi-allelic pathogenic POC1A variants. Design: Observational study. Methods: Probands’ phenotypes, including short stature, dysmorphism and insulin resistance, were...

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Skeletal maturation can be delayed by reducing the exposure to estrogens, either by halting pubertal development through administering a GnRH analogue (GnRHa), or by blocking the conversion of androgens to estrogens through an aromatase inhibitor (AI). These agents have been investigated in children with growth disorders (off-label), either alone o...

Coats plus syndrome is an autosomal recessive multisystemic and pleiotropic disorder affecting the eyes, brain, bone, and gastrointestinal tract, usually caused by compound heterozygous variants of the Conserved Telomere maintenance Component 1 gene (CTC1), involved in telomere homeostasis and replication. So far, most reported patients are compoun...

Inleiding: Het doel van dit onderzoek was het ontwikkelen van een richtlijn voor Jeugdgezondheidszorg (JGZ)-professionals om aandoeningen die samenhangen met een kleine lengte (en/of trage groei) of een grote lengte (en/of snelle groei) vroegtijdig op te sporen. Methode: Op basis van literatuur en advies van een expertcommissie werd de vorige JGZ-r...

Human growth is a complex trait. A considerable number of gene defects have been shown to cause short stature, but there are only few examples of genetic causes of non-syndromic tall stature. Besides rare variants with large effects and common risk alleles with small effect size, oligogenic effects may contribute to this phenotype. Exome sequencing...

The current differential diagnosis for a short child with low insulin-like growth factor I (IGF-I) and a normal growth hormone (GH) peak in a GH stimulation test (GHST), after exclusion of acquired causes, includes the following disorders: (1) a decreased spontaneous GH secretion in contrast to a normal stimulated GH peak (“GH neurosecretory dysfun...

Objectives We performed a cross-sectional study on anthropometric and laboratory characteristics of inhabitants of Rampasasa (Flores, Indonesia). Adults were categorised according to ancestry into three groups: pygmoid (P/P, offspring of pygmoid parents, n=8), mixed pygmoid (P/N, offspring of pygmoid and non-pygmoid parents, n=12) and non-pygmoid (...

Loss of function mutations in the X-linked immunoglobulin superfamily, member 1 (IGSF1) gene result in central hypothyroidism, often associated with macroorchidism. Testicular enlargement in these patients might be caused by increases in follicle-stimulating hormone (FSH) levels, as IGSF1 has been proposed to function as an inhibin B receptor or as...

The terms idiopathic short stature (ISS) and small for gestational age (SGA) were first used in the 1970s and 1980s. ISS described non-syndromic short children with undefined aetiology who did not have growth hormone (GH) deficiency, chromosomal defects, chronic illness, dysmorphic features or low birth weight. Despite originating in the pre-molecu...

Signal peptide-CUB-EGF domain-containing protein 3 (SCUBE3) is a member of a small family of multifunctional cell surface-anchored glycoproteins functioning as co-receptors for a variety of growth factors. Here we report that bi-allelic inactivating variants in SCUBE3 have pleiotropic consequences on development and cause a previously unrecognized...

Signal peptide-CUB-EGF domain-containing protein 3 (SCUBE3) is a member of a small family of multifunctional cell surface-anchored glycoproteins functioning as co-receptors for a variety of growth factors. Here we report that bi-allelic inactivating variants in SCUBE3 have pleiotropic consequences on development and cause a previously unrecognized...

Human growth is a complex trait determined by genetic factors in combination with external stimuli, including environment, nutrition and hormonal status. In the past, several genome-wide association studies (GWAS) have collectively identified hundreds of genetic variants having a putative effect on determining adult height in different worldwide po...

Aim To develop a guideline for preventive child healthcare professionals in order to improve early detection of pathological disorders associated with short stature (or growth faltering) or tall stature (or accelerated growth). Methods We updated the previous Dutch guideline for short stature in children aged 0‐9 years and extended it to adolescent...

Our objective is to further expand the spectrum of clinical characteristics of the IGSF1 deficiency syndrome in affected males, which so far includes congenital central hypothyroidism, disharmonious pubertal development (normally timed testicular growth, but delayed rise of serum testosterone), macroorchidism, increased body mass index, decreased a...

Assessment and management of children with growth failure has improved greatly over recent years. However, there remains a strong potential for further improvements by use of novel digital techniques. A panel of experts discussed developments in digitalization of a number of important tools used by pediatric endocrinologists at the third 360° Europ...

Background/aims: We hypothesized that modelling catch-up growth (CUG) as developed for coeliac disease (CD), might also fit CUG in adequately treated children with juvenile hypothyroidism (JHT) or growth hormone deficiency (GHD). Methods: We used a monomolecular function for all available prepubertal data on height SDS minus target height SDS (a...

The insulin-like growth factor (IGF) system comprises two ligands, IGF-I and IGF-II, that regulate multiple physiological processes, including mammalian development, metabolism and growth, through the type 1 IGF receptor (IGF-1R). The growth hormone (GH)-IGF-I axis is the major regulator of longitudinal growth. IGF-II is expressed in many tissues,...

Background/objectives: In the clinical assessment of a short or tall child, estimating body disproportion is useful to assess the likelihood of a primary growth disorder, e.g., skeletal dysplasia. Our objectives were (1) to use data from the Maastricht study on healthy children (2-17 years) to calculate relative arm span (AS) for height (H) to ser...

In this case series, we describe four children and adolescents with tall stature or growth acceleration to illustrate the diagnostic evaluation of tall stature according to the new Paediatric Association of the Netherlands (NVK) Guideline on growth disorders. A 14-year-old girl with tall stature and a relatively late onset of puberty was diagnosed...

The serum insulin-like growth factor-I (IGF-I) concentration is commonly used as a screening tool for growth hormone deficiency (GHD), but there is no consensus on the cut-off limit of IGF-I standard deviation score (SDS) to perform GH stimulation tests for confirmation or exclusion of GHD. We argue that the cut-off limit is dependent on the clinic...

Isolated growth hormone (GH) deficiency (IGHD) type 2 is a rare autosomal dominant disorder characterized by severe short stature with low GH level. Timely diagnosis is important for optimal results of recombinant human GH (rhGH) treatment and detection of additional pituitary deficiencies in affected relatives. A male child presented at the age of...

Context The X-linked immunoglobulin superfamily, member 1 (IGSF1) gene is highly expressed in the hypothalamus and in pituitary cells of the POU1F1 lineage. Human loss-of-function mutations in IGSF1 cause central hypothyroidism, hypoprolactinemia, and macroorchidism. Additionally, most affected adults exhibit higher than average IGF-1 levels and an...

IGF deficiency caused by a homozygous loss-of-function of IGF1 is a very rare cause of growth failure. This paper comments on an original research paper in this issue on a novel patient with this condition, confirming its main clinical features (severe prenatal and postnatal growth failure, severe microcephaly, retrognathia, sensorineural deafness...

The Growth Hormone Research Society (GRS) convened a Workshop in March 2019 to evaluate the diagnosis and therapy of short stature in children. Forty-six international experts participated at the invitation of GRS including clinicians, basic scientists, and representatives from regulatory agencies and the pharmaceutical industry. Following plenary...

Three recent publications in this journal have reported that the differences in IGF-1 normative data significantly impact the classification of patients with growth hormone (GH)- excess and deficiency disorders in such a way that clinical performance is severely flawed. This concerns not only pediatric but also adult patients. With this letter, we...

Tall stature and/or accelerated growth (TS/AG) in a child can be the result of a primary or secondary growth disorder, but more frequently no cause can be found (idiopathic TS). The conditions with the most important therapeutic implications are Klinefelter syndrome, Marfan syndrome and secondary growth disorders such as precocious puberty, hyperth...

It is over sixty years since the first administration of human growth hormone (GH) to children with GH deficiency, and over thirty years since recombinant human GH has been available for treatment of GH deficiency and a wider range of non-GH deficiency disorders. From a diagnostic perspective, genetic analysis, using single gene or Sanger sequencin...

Based on a recent Dutch national guideline, we propose a structured stepwise diagnostic approach for children with growth failure (short stature and/or growth faltering), aiming at high sensitivity for pathologic causes at acceptable specificity. The first step is a detailed clinical assessment, aiming at obtaining relevant clinical clues from the...

[Update Sept 2021: A new report of the Dutch Bureau of Statistics CBS reports that the Dutch are still the tallest in the world. However, the generation born in 1980 is the tallest, but later generations are a bit smaller. So the average Dutch is shrinking a bit. End update]. The Dutch have developed into the tallest people in the world. For a cent...

Background: Various prediction models for the growth response to recombinant human growth hormone (rhGH) have been published, but none of these have been able to incorporate data on adherence to rhGH treatment. Previous studies have shown that suboptimal adherence negatively affects the growth response in the first two years of rhGH treatment. The...

[Update sept. 2021: Uit een nieuw rapport van het CBS blijkt dat Nederlanders nog steeds de langste ter wereld zijn. De generatie geboren in 1980 is echter de langste, maar latere generaties zijn iets kleiner. Nederlanders hebben zich ontwikkeld tot de langste mensen in de wereld. Die toename van lichaamslengte vindt al anderhalve eeuw plaats. Verr...

Context The phenotype and response to growth hormone (GH) treatment of children with a IGF1R defect is insufficiently known. Objective To develop a clinical score for selecting short children for genetic testing and evaluate the efficacy of treatment. Design, setting Case series with an IGF1R defect identified in a university genetic laboratory....

Objective: Insulin like growth factors-1 (IGF-1) is essential for normal in utero and postnatal human growth. It mediates its effects through the IGF-1 receptor (IGF1R), a widely expressed cell surface tyrosine kinase receptor. The aim of the study was to analyze pre- and post-natal growth, clinical features and laboratory findings in a small for...

Introduction: Short stature homeobox-containing gene (SHOX) haploinsufficiency is associated with short stature, Madelung deformity and mesomelia. Current clinical screening tools are based on patients with intragenic variants or deletions. However, recent discoveries showed that deletions of the enhancer elements are quite common. The majority of...

Background Quantifying the association between adherence and the growth response to growth hormone (GH) treatment is hampered by suboptimal methods of measuring adherence, confounders associated with the growth response, and restriction of the outcome parameters to yearly growth velocities. Aim To investigate the effect of adherence on the two-yea...

Context: Small for gestational age (SGA) can be a result of fetal growth restriction, associated with perinatal morbidity and mortality. Mechanisms that control prenatal growth are poorly understood. Objective: The aim of the present study was to gain more insight into prenatal growth failure and determine an effective diagnostic approach in SGA ne...

Children born small-for-gestational age (SGA), defined as a birth weight and/or length <-2 SDS, comprise a heterogeneous group. The causes of SGA are multifactorial and include maternal life-style and obstetric factors, placental dysfunction, and numerous fetal (epi)genetic abnormalities. Short-term consequences of SGA include increased risks of hy...

The natriuretic peptide signaling pathway has been implicated in many cellular processes, including endochondral ossification and bone growth. More precisely, different mutations in the NPR-B receptor and the CNP ligand have been identified in individuals with either short or tall stature. In this study we show that the NPR-C receptor (encoded by N...

Objective: The Insulin-like growth factor 1 receptor (IGF-1R) is important in growth and development, and inactivating IGF1R mutations cause short stature and relatively high levels of serum IGF-I. We identified an unclassified IGF1R R1353H variant in a male with extreme tall height, very low levels of serum IGF-I and delayed and prolonged growth...

Aims/hypothesis: Gestational diabetes mellitus (GDM) is reported to be associated with childhood obesity, however the magnitude of this association and relation to intrauterine growth is uncertain. We, therefore, aimed to assess whether the growth trajectories of large for gestational age (LGA) and non-LGA offspring of mothers with GDM (OGDM) are...

Om gezinnen met een hoog risico op kindermishandeling vroegtijdig op te sporen werd een actuarieel screeningsinstrument ontwikkeld genaamd Screeningsvragenlijst Stevig Ouderschap. Het doel van deze studie was de predictieve validiteit van dit instrument te onderzoeken en te vergelijken met de predictieve validiteit van een klinische risico-inschatt...

Immunoglobulin superfamily, member 1 (IGSF1) is a transmembrane glycoprotein, highly expressed in the mammalian pituitary gland. Shortly after its discovery in 1998, the protein was proposed to function as a co-receptor for inhibins (and was even temporarily re-named inhibin binding protein). However, subsequent investigations, both in vitro and in...

Context Small for gestational age (SGA) can be a result of fetal growth restriction, associated with perinatal morbidity and mortality. Mechanisms that control prenatal growth are poorly understood. Objective The aim of the present study was to gain more insight into prenatal growth failure and determine an effective diagnostic approach in SGA new...

For preventive purposes it is important to be able to identify families with a high risk of child maltreatment at an early stage. Therefore we developed an actuarial instrument for screening families with a newborn baby, the Instrument for identification of Parents At Risk for child Abuse and Neglect (IPARAN). The aim of this study was to assess th...

We present a 13-year-old boy who became progressively sleepy and experienced a sudden headache with vomiting and fever. Laboratory testing showed hypoglycemia, multiple pituitary hormonal deficiencies and elevated C-Reactive Protein (CRP). A cranial MRI showed an opaque sphenoid sinus and an intrasellar mass suspect for hemorrhage, so that we suspe...

Cornelia de Lange Syndrome (CdLS) is a heterogeneous syndrome, both clinically and genetically, in its classical form characterised by distinctive facial features, intra-uterine growth retardation, short stature, developmental delay and anomalies in multiple organ systems. NIPBL, SMC1A, SMC3, RAD21 and HDAC8, all involved in the Cohesin pathway, ha...

Background: Childhood obesity is associated with advanced bone age (BA). Previous studies suggest that androgens, oestrogens, sex hormone-binding globulin, and insulin are responsible for this phenomenon, but results are contradictory and might be biased by confounders. We aim to elucidate this matter by applying a multivariate approach. Method:...

Objective: Acid Labile Subunit (ALS) deficiency (ACLSD), caused by homozygous or compound heterozygous IGFALS mutations, is associated with moderate short stature, delayed puberty, low serum IGF-I and ALS and extremely low serum IGFBP-3. The effect on birth weight, head circumference, bone mineral density (BMD), serum IGF-II and IGFBP-2 is uncerta...

Background/aims: Childhood stunting is a prevalent problem in low- and middle-income countries and is associated with long-term adverse neurodevelopment and health outcomes. In this review, we define indicators of growth, discuss key challenges in their analysis and application, and offer suggestions for indicator selection in clinical research co...

Loss-of-function mutations in the X-linked immunoglobulin superfamily, member 1 (IGSF1) gene cause central hypothyroidism. IGSF1 is a transmembrane glycoprotein of unknown function expressed in TSH-producing thyrotrope cells of the anterior pituitary gland. The protein is co-translationally cleaved, with only its C-terminal domain (CTD) being traff...

BACKGROUND Infants of women with pregestational diabetes are at risk for developing obesity in later life. This study aimed to identify subgroups at highest risk, by studying growth profiles of offspring from women with type 1 or 2 diabetes mellitus (ODM1, ODM2) until the age of 14 years.METHODS Information from infant welfare centers was received...

Background/aims: Increasing agreement exists about the use of length-for-age as the indicator of choice in monitoring the long-term impact of chronic nutritional deficiency. Yet, already shortly after World War I, a causal link between nutrition and growth was questioned. Also, modern meta-analyses of controlled nutrition intervention studies show...

Context: Isolated congenital central hypothyroidism (CeH) can result from mutations in TRHR, TSHB and IGSF1, but its etiology often remains unexplained. We identified a missense mutation in the Transducin β-like protein 1, X-linked (TBL1X) gene in three relatives diagnosed with isolated CeH. TBL1X is part of the thyroid hormone receptor corepresso...

In approximately 10 % of children with isolated growth hormone deficiency, a genetic defect can be found. Traditionally, familial isolated growth hormone deficiency (IGHD) has been classified into four types, depending on the inheritance pattern. We propose to use an adapted classification which is first based on the gene defect (GHRHR or GH1). For...

Early diagnosis is a key objective in clinical medicine, and early detection of pathological short stature has tangible benefits for growth prognosis and the well-being of the child. Despite late diagnosis being common in growth disorders, programmes of height screening in primary care are not universal in developed countries and may be random or n...

Insulin-like growth factors (IGF) are critical for normal intrauterine and childhood growth and sustaining health throughout life. We showed previously that production of IGF-I and -II requires interaction with the chaperone Glucose Regulated Protein 94 (GRP94) and that the amount of secreted IGFs is proportional to the GRP94 activity. Therefore, w...

Background: Recessive mutations in the leptin receptor (LEPR) are a rare cause of hyperphagia and severe early-onset obesity. To date, the phenotype has only been described in 25 obese children, some of whom also had altered immune function, hypogonadotropic hypogonadism, reduced growth hormone secretion, hypothalamic hypothyroidism or reduced adu...

Context: Mutations in the immunoglobulin superfamily, member 1 (IGSF1) gene cause the X-linked IGSF1 deficiency syndrome consisting of central hypothyroidism, delayed pubertal testosterone rise, adult macroorchidism, variable prolactin deficiency, and occasionally transient partial GH deficiency. Since our first reports, we discovered 20 new famil...

The aim of the study was to evaluate the etiology, the role of pubertal timing and most useful criteria for diagnostic workup in adolescents with growth failure. Adolescents (n=182) aged 10.0–18.0 years underwent a standardized diagnostic protocol. Constitutional delay of growth and puberty (CDGP) was defined as late pubertal onset or a Tanner stag...

Patient: A male patient had been treated since the age of 9 years with GH and thyroxine for an idiopathic combined GH, TSH and PRL deficiency. His GH deficiency proved transient upon stopping GH at 19 years old, but deficiencies of TSH and PRL persisted and he had developed macro-orchidism since the end of puberty. Brain MRI and PROP1 and POU1F1 s...

Objective: No evidence-based guideline has been published about optimal referral criteria and diagnostic work-up for tall stature in children. The aim of our study was to describe auxological and clinical characteristics of a cohort of children referred for tall stature, to identify potential candidates for adult height reduction, and to use these...

The fast technological development, particularly SNP array, array-comparative genomic hybridization and whole exome sequencing, has led to the discovery of many novel genetic causes of growth failure. In this review we discuss a selection of these, according to a diagnostic classification centred on the epiphyseal growth plate. We successively disc...

This is the author accepted manuscript. It is currently embargoed pending publication.

Aims: To evaluate three guidelines for selecting short children for diagnostic workup in a general pediatric clinic. Methods: All patients (n = 131) aged 3.00-9.99 years who were referred for growth failure to a general pediatric clinic were evaluated for their medical history and growth and examined. All of them underwent the same standardized...

In the past, the growth hormone (GH)-insulin-like growth factor 1 (IGF-1) axis was often considered to be the main system that regulated childhood growth and, therefore, determined short stature and tall stature. However, findings have now revealed that the GH-IGF-1 axis is just one of many regulatory systems that control chondrogenesis in the grow...

Objective: Male patients with the X-linked IGSF1 deficiency syndrome are characterized by central hypothyroidism, delayed pubertal testosterone rise, adult macroorchidism, variable prolactin deficiency and occasionally transient partial growth hormone deficiency. Thyroid hormone plays a vital role in brain development and functioning, and while mo...

Objective: To answer the questions: Are perinatal reproductive hormone profiles different in case of a twin compared with a singleton pregnancy? Are reproductive endocrine profiles of twin girls influenced by their male co-twin and vice versa? Design: Prospective cohort study from January 2004 to October 2009. Setting: Not applicable. Patient...

Objective: Short stature caused by point mutations or deletions of the short stature homeobox (SHOX) gene (SHOX haploinsufficiency (SHI)) is a registered indication for GH treatment. Patients with a SHOX enhancer deletion (SED) have a similar phenotype, but their response to GH is unknown. It is uncertain if duplications of SHOX or its enhancer (S...

The accretion of bone mass is often impaired in preterm infants, which may contribute to postnatal growth failure. We tested the effects of the vitamin D receptor single-nucleotide polymorphisms (SNPs) c1521g, Fok1, Bsm1, and Taq1 on linear growth up until adulthood in 341 subjects born very prematurely (i.e., <32 weeks of gestation) from the Dutch...

Loss-of-function mutations in the immunoglobulin superfamily member 1 (IGSF1) gene cause an X-linked syndrome of central hypothyroidism, macroorchidism, variable prolactin and GH deficiency, delayed pubertal testosterone rise, and obesity. To understand the pathophysiology of this syndrome, knowledge on IGSF1's place in normal development is impera...