Cowden Syndrome
Dongyou Liu in Handbook of Tumor Syndromes, 2020
(i) multiple hamartomas,(ii) macrocephaly (enlarged head) and dolichocephaly, and(iii) other tumors. Multiple hamartomas are small, noncancerous growths that are most commonly found on the skin and mucous membranes (e.g., the lining of the mouth, nose, and intestines) as well as other organs (the thyroid, breast, and brain). Four hallmark cutaneous features of Cowden syndrome are papules in the face, acral keratoses, mouth lesions, and palmoplantar keratoses (Figure 90.1). Specifically, the papules in the face are skin eruptions through infiltration of the dermis and epidermis area; predominantly located in areas surrounding an orifice, these lesions (so-called facial trichilemmomas) appear flat at the top and flesh-like in color, and measure 1–5 mm in size with the center containing a keratin material. Acral keratoses are often found on the backs of the feet and hands of >50% of patients. Mouth lesions are represented by noncancerous papules (smooth, white in color, 1–3 mm in diameter) that band together to form a cobblestone-like exterior on the surfaces of the palate and the gingiva, or make the tongue wrinkled and thickened. Palmoplantar keratoses (acanthosis, dense orthokeratosis, prominent granular layer) are transparent and spotted punctures in the soles of the feet and in the hands of 50% of patients. Some patients may display visual problems (e.g., myopia), atypical facial features (e.g., abnormally small jaw, uncharacteristically high-domed palate), mental retardation, genitourinary system malformation, and esophageal glycogenic acanthosis. Patients with Cowden syndrome are at increased risk of developing cancers of the breast, thyroid, uterus (endometrial), kidney, and colorectum. Benign breast conditions (e.g., ductal hyperplasia, intraductal papillomatosis, adenosis, lobular atrophy, fibroadenomas, and fibrocystic changes) and thyroid abnormalities (e.g., noncancerous adenomas, goiter, and cysts) may occur in up to 75% and over 50% of patients, respectively. Females with a PTEN pathogenic variant have an 85% lifetime risk for breast cancer, and penetrance of 50% by 50 years of age. Patients also show a 35% lifetime risk for epithelial thyroid cancer, with a median age of onset at 37 years; however, no medullary thyroid carcinoma is observed. Further, patients have a 28% lifetime risk for endometrial cancer, with an onset age between the late 30s and early 40s. Over 90% of individuals with a PTEN pathogenic variant develop polyps (ranging from ganglioneuromatous polyps, hamartomatous polyps, and juvenile polyps to adenomatous polyps) and have a 9% lifetime risk for colorectal cancer, with an onset age in the late 30s. Patients also have a 35% lifetime risk for renal cell carcinoma (predominantly of papillary histology), with an onset age of the 40s [18–22].
Central nervous system: Paediatric and neurodevelopmental disorders
Angus Clarke, Alex Murray, Julian Sampson in Harper's Practical Genetic Counselling, 2019
Macrocephaly (to be distinguished from hydrocephalus) may be part of a neurological disorder (e.g. neurofibromatosis, various cerebral degenerations), or part of a more general growth disorder (e.g. Sotos syndrome and the PTEN/Cowden syndrome, with some risk of malignancy, and others), or an isolated feature usually not associated with serious consequences, and commonly autosomal dominant. It may sometimes be associated with autism. Fragile X syndrome should also be considered as a possible cause in the presence of intellectual disability.
D-2-hydroxyglutaric (DL-2-hydroxyglutaric) aciduria
William L. Nyhan, Georg F. Hoffmann, Aida I. Al-Aqeel, Bruce A. Barshop in Atlas of Inherited Metabolic Diseases, 2020
Developmental retardation is a common feature of these diseases. Many patients are not yet known to have type 1, type 2, or type 3. In 17 patients with the severe phenotype, manifestations were early onset: at 7 months, one [1] could not sit or roll and did not fix or follow; another [3] was cortically blind. Most of the patients classified as severe [4, 5] had little evidence of mental development. Among the patients with milder presentations, mental retardation and hypotonia were the rules, though the younger sister of one patient appeared by three years to have only speech delay, and both sisters were dysmorphic, suggesting the possibility of another etiology for the mental retardation [1]. The clinical phenotype was set out by van der Knaap and associates [4] in an international survey of 25 patients with documented D-2-hydroxyglutaric aciduria. The first symptom may be vomiting. In three patients [1, 5], it was sufficiently severe that a diagnosis of pyloric stenosis was made and a pyloromyotomy performed. A number of metabolic diseases, particularly organic acidemias that present in the neonatal period may be diagnosed as pyloric stenosis or similar surgical disease (see Appendix). Macrocephaly may be another early symptom [1] (Figure 11.3). At seven months, the head circumference in one patient at 47 cm was in the fiftieth percentile for 19 months. This patient also had chronic subdural collections of fluid. Macrocephaly was also present in three of the patients classified as mild [5]; and four of the severe patients became microcephalic. Macrocephaly and subdural collections of fluid are also characteristic of glutaric aciduria resulting from glutarylCoA dehydrogenase deficiency (Chapter 9), and these diseases should be considered (Appendix) before a diagnosis of nonaccidental trauma is made. Seizures may be grand mal or myoclonic; some were of neonatal onset, and abnormalities [1, 3] of the electroencephalogram (EEG) included hypsarrhythmia [1]. The concentration of protein in the cerebrospinal fluid (CSF) may be increased [1]. Cerebral blindness or delayed cerebral visual development has been observed [3–5]. Involuntary movements described have included chorea, dystonic posturing and episodic opisthotonic arching and extensor posturing [1, 3, 5]. Hypotonia has been observed in a number of patients [1, 3, 5], but there may also be hypertonia. Irritability and lethargy have been observed.
Fetal wide subarachnoid space and its outcome in cases of macrocephaly without ventriculomegaly
Published in The Journal of Maternal-Fetal & Neonatal Medicine, 2020
Joel Baron, Salvatore Andrea Mastrolia, Ilan Shelef, Dan Tirosh, Analia Mijalovsky, Yigal Ben-Harush, Reli Hershkovitz
Objective: To examine the occurrence and outcomes of fetuses with wide subarachnoid space (WSS) without ventriculomegaly in pregnant women with fetal macrocephaly as a sole diagnosis. Study design: A retrospective study was performed, analyzing patients with fetal macrocephaly between the years 2008 and 2018. All these patients underwent MRI, in order to detect brain anomalies. In the absence of any other brain abnormality, they were evaluated for WSS and their offspring’s database was followed for at least two years after birth. Results: Ten patients were found to be carrying fetuses with macrocephaly, nine of them were diagnosed with WSS without ventriculomegaly prior to delivery. Following at least two years of follow up, all patients did not present significant neurodevelopmental abnormalities, apart from one child that had a genetic mutation of 15q21.2-22.31 deletion with other anomalies that were not diagnosed prenatally. Conclusions: We present herein for the first time in the literature a cohort of patients with a prenatal diagnosis of WSS without ventriculomegaly in fetuses with macrocephaly. Our data show that, in the presence of normal anomaly scan and normal chromosomal study, there is a low chance for significant neurodevelopmental abnormalities in fetuses with WSS without ventriculomegaly.
A spontaneous pregnancy and successful delivery in a Chinese female with Silver-Russell syndrome accompanied by gestational diabetes mellitus
Published in Gynecological Endocrinology, 2019
Mengte Shi, Luya Ruan, Xiaomin Shi, Yaoxin Zhu, Yanying Qian, Zhijuan Dai, Chaoming Wu
Silver-Russell syndrome (SRS) is a heterogeneous disorder characterized by severe intrauterine and postnatal growth retardation and typical dysmorphic features including body asymmetry, relative macrocephaly, protruding forehead, and feeding difficulties. Previous descriptions of SRS focus on the management of specific issues in children. Herein, we present clinical and metabolic characteristics of an adult woman with SRS accompanied by gestational diabetes mellitus (GDM). Given the rare circumstances presented in our case, the emerging questions concerning the management of metabolic issues and fertility potential in adult SRS patient deserve more attention. Further, long-term follow up is essential to gain future insights into the natural history and optimal management in adulthood.
Volumetric and Voxel-Based Morphometry Findings in Autism Subjects With and Without Macrocephaly
Published in Developmental Neuropsychology, 2010
Erin Bigler, Tracy Abildskov, Jo Petrie, Michael Johnson, Nicholas Lange, Jonathan Chipman, Jeffrey Lu, William McMahon, Janet Lainhart
This study sought to replicate Herbert et al. (2003a), which found increased overall white matter (WM) volume in subjects with autism, even after controlling for head size differences. To avoid the possibility that greater WM volume in autism is merely an epiphenomena of macrocephaly overrepresentation associated with the disorder, the current study included control subjects with benign macrocephaly. The control group also included subjects with a reading disability to insure cognitive heterogeneity. WM volume in autism was significantly larger, even when controlling for brain volume, rate of macrocephaly, and other demographic variables. Autism and controls differed little on whole-brain WM voxel-based morphometry (VBM) analyses suggesting that the overall increase in WM volume was non-localized. Autism subjects exhibited a differential pattern of IQ relationships with brain volumetry findings from controls. Current theories of brain overgrowth and their importance in the development of autism are discussed in the context of these findings.
Related Knowledge Centers
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