Pallister-Hall syndrome, firstly described 40 years ago, is an extremely rare genetic disorder [1] [2] [3] [4]. The pathogenesis stems from mutations in the GLI3 gene on chromosome 7p13, which is involved in the sonic hedgehog pathway, a key signaling process of cell maturation [1] [3] [5]. So far, the majority of cases have been described as familial with an autosomal dominant pattern of inheritance [1] [3]. The nature of the disorder causes signs and symptoms to be evident from birth. Several key features comprise Pallister-Hall syndrome [1] [2] [3] [4] [5] [6]:

• Polydactyly - The presence of additional fingers arising from the ulnar/fibular parts of the limbs is a crucial clinical finding in this patient population, often accompanied by dysplasia of the nails [1].
• Hypothalamic hamartoma - Hamartomas can be quite large (up to several centimeters in length) and produce seizures. The term "gelastic epilepsy" is used to describe a specific type of a partial complex seizure that presents with clonic movements of the diaphragm and chest and mimic laughing [1]. Other neurological deficits, growth hormone deficiency, or even precocious puberty has been attributed to hamartomas, but many patients are surprisingly asymptomatic [1] [6]. In fact, surgical treatment is often contraindicated due to consequent hypopituitarism and several other complications. In rare patients who develop Pallister-Hall syndrome in a sporadic fashion, deficiency of cortisol might be encountered [1].
• Bifid epiglottis - In the majority of cases, this anatomical abnormality is asymptomatic, but severe derangements lead to dangerous airway obstruction and death without early treatment [1] [3].

Additional signs and symptoms include renal malformation (hypoplasia, agenesis, ectopic kidneys, or development of cysts), genitourinary changes (imperforate anus, hydrometrocolpos), and skeletal changes such as short limbs [1] [3] [6].

• Short Stature

  We conclude that children with Pallister-Hall syndrome and short stature be evaluated carefully for spontaneous somatotropic function and, if necessary, treated with growth hormone. [ncbi.nlm.nih.gov]

  Idiopathic short stature (ISS) Idiopathic short stature is characterized by significant short stature ( rd percentile for height will be found to be growth hormone deficient or have mutations involving growth hormone releasing hormone (GHRH), GH, IGF- [hormones.gr]

  On examination, he had dysmorphic facies with bulbous nose tip, small stubby hands with central polydactyly and short stature. The MRI of the brain showed a hypothalamic hamartoma. [longdom.org]

  stature, and intellectual disabilities) 759.89 Rud's (mental deficiency, epilepsy, and infantilism) 759.89 Russell (-Silver) (congenital hemihypertrophy and short stature) 759.89 Seckel's 759.89 sick Silver's (congenital hemihypertrophy and short stature [icd9data.com]

  Hall specialized in the genetic factors that affect lack of children’s growth, including the mechanism of neural tube defects, the genetics of short stature and the genetics of connective tissue disorders such as arthrogryposis, dwarfism, and monozygotic [cdnmedhall.org]

• Swelling

  […] develop giving the primitive glottis a T-shaped appearance and reducing the laryngeal lumen to a slit laryngeal cartilages develop within the arytenoid swellings from the cartilage bars of the branchial arches (epiglottis develops from the caudal half [laryngeal-cleft.com]

  29993343 ) Zare S...Hemmatjo R 2018 16 Protein-Resistant Property of Egg White Ovomucin under Different pHs and Ionic Strengths. ( 30277391 ) Sun X...Wu J 2018 17 Antibacterial oxidized starch/ZnO nanocomposite hydrogel: Synthesis and evaluation of its swelling [malacards.org]

  Background An abscess is a collection of pus in any part of the body that is surrounded by swelling and inflammation. An abscess may develop, enlarge, or subside, depending upon the degree of infection by microorganisms, such as bacteria. [livingnaturallyonline.com]

• Dysmorphic Face

  face in the form of small ears pointing backwards, small retroverted nose, with flat nasal bridge, vertical groove in the middle of the upper lip philtrum, small tongue, and hypothalamic hamartomas causing hypopituitarism, micropenis, lethargy, hypoglycemia [pediatricneurosciences.com]

• Pallor

  pallors pallors Pallotti High School Pallottino, Massimo palls palls palls Pallu pally pally pally ▼ [medical-dictionary.thefreedictionary.com]

• Macrocephaly

  The major anomalies of GCPS include macrocephaly with hypertelorism and polydactyly. Both have variable expressivity but are clinically distinct. GLI3 encodes a zinc finger transcription factor in the sonic hedgehog (SHH) pathway. [oxfordmedicine.com]

  Acrocallosal syndrome Characterized by macrocephaly, hypertelorism, seizures, and mental retardation. [pediatricneurosciences.com]

  Tests Available GLI3 Gene Sequencing & Del/Dup Syndromic Macrocephaly/Overgrowth Panel Forms and Documents Test Details Clinical Utility: Confirmation of a clinical diagnosis Carrier testing Ordering Preferred Specimen: 2-5 mL Blood - Lavender Top Tube [genedx.com]

• Hypertelorism

  No reported cases of GCPS have hypothalamic hamartoma and PHS does not cause hypertelorism or broadening of the nasal root or forehead. The co-localization of the loci for PHS and GCPS led us to investigate GLI3 as a candidate gene for PHS. [ncbi.nlm.nih.gov]

  The major anomalies of GCPS include macrocephaly with hypertelorism and polydactyly. Both have variable expressivity but are clinically distinct. GLI3 encodes a zinc finger transcription factor in the sonic hedgehog (SHH) pathway. [oxfordmedicine.com]

  Acrocallosal syndrome Characterized by macrocephaly, hypertelorism, seizures, and mental retardation. [pediatricneurosciences.com]

• Kidney Failure

  Use sodium iodide cautiously with kidney failure. Avoid sodium iodide with gastrointestinal obstruction. Iodine is considered to be safe in recommended doses for pregnant or breastfeeding women. [livingnaturallyonline.com]

Because of the very rare occurrence of Pallister-Hall syndrome in general practice, the diagnosis may be difficult to attain. For this reason, an early clinical workup is critical in order to recognize the key elements of this disorder. Physicians should first obtain a detailed patient history that will cover the onset of symptoms and their progression. A detailed family history must not be overlooked because of the autosomal dominant pattern of inheritance. After history taking, the physical examination can discover polydactyly and additional anatomical changes, but in order to solidify the diagnosis and obtain additional evidence toward Pallister-Hall syndrome, imaging studies are necessary. The cardinal feature, hypothalamic hamartoma, is best seen through magnetic resonance imaging (MRI), as neither computed tomography (CT) nor cranial ultrasonography are able to detect it [1]. A non-calcified and non-enhancing mass, usually located behind the optic chiasm and on the third ventricle floor, exhibits an isointense signal on T1 and T2-weighted studies [1] [3]. Molecular genetic techniques, which are able to detect the mutated GLI3 gene on chromosome 7, serve as the definitive method for diagnosing Pallister-Hall syndrome [1].

GH deficiency was confirmed and GH treatment was initiated at the age of 4 years. However, we were concerned about the safety of GH treatment because of the possible stimulating effect of GH on tumor regrowth. [jmedicalcasereports.biomedcentral.com]

Management and treatment Treatment is symptomatic. Medical imaging should include MRI to assess the hypothalamic hamartoma, X-rays of hands and feet and a full-skeletal survey as well as renal ultrasound. [orpha.net]

Treatment Treatment of individuals with PHS depends on their individual manifestations. Management of epiglottic abnormalities depends on the type of abnormality and extent of respiratory compromise. Seizures are treated symptomatically. [atlasgeneticsoncology.org]

Standard treatment of anal atresia or stenosis; symptomatic treatment of seizures; elective repair of polydactyly; developmental intervention or special education for developmental delays. [ncbi.nlm.nih.gov]

Make the best clinical decisions with an enhanced emphasis on evidence-based practice and expert opinions on treatment strategies. Zero in on the most relevant and useful references with the aid of a more focused, concise bibliography. [books.google.com]

Treatment and prognosis Prognosis in those with no known family history is based on the severity of the malformations present. [radiopaedia.org]

Prognosis The prognosis for an individual with PHS and no known family history of PHS is based on the malformations present in the individual. [atlasgeneticsoncology.org]

This patient's phenotype was complex with unusual gastrointestinal features ultimately leading to a unfavorable prognosis and outcome, highlighting the range of clinical severity in patients with Pallister-Hall syndrome. [ncbi.nlm.nih.gov]

Prognosis - Pallister-Hall syndrome Because of the broad range and severity of Pallister-Hall signs and symptoms, the prognosis varies widely from case to case. [checkorphan.org]

Prognosis Prognosis should be assumed to be excellent until proven otherwise. However, in its most severe forms, panhypopituitarism and severe airway malformations can be lethal; imperforate anus may also be lethal if not recognized. [orpha.net]

The known genetic parallels between these conditions is discussed briefly in terms of etiology. [ncbi.nlm.nih.gov]

The original reference is provided for historical interest, and review articles are included to show recent advances in etiology and treatment. [books.google.com]

[…] polydactyly midline facial capillary hemangioma nail dysplasia cerebral anomalies holoprosencephaly hypothalamic hamartoblastoma pituitary aplasia or dysplasia endocrine anomalies pan hypopituitarism adrenal gland hypoplasia thyroid dysplasia/aplasia Etiology [humpath.com]

We aim to use the power of modern molecular genetics and clinical research to delineate the range of severity, natural history, molecular etiology, and pathophysiology of a number of congenital anomaly syndromes. [clinicaltrials.gov]

Etiology PHS is due to mutations of the GLI3 gene (7p13) that encodes a transcription factor activated by the sonic hedgehog pathway. Mutations lead to alterations in gene expression during development. [orpha.net]

These include PhD programs in Epidemiology and Health Services Research, Master's programs in Public Health, Epidemiology, Clinical Investigation, and Health Services Research, and 6 Advanced Certificates in Epidemiology, Health Services Research, Biomedical [urmc.rochester.edu]

The protocol for data collection included epidemiological aspects, as well as immediate and late complications. RESULTS: ninety-six patients were enrolled. [ncbi.nlm.nih.gov]

Summary Epidemiology Approximately 100 patients have been reported to date. [orpha.net]

Richter 1955 first successful repair by Pettersson 1979 first endoscopic repair by Yamashita 1987 Tucker described submucouscleft 1989 Benjamin and Inglisdeveloped classification system most widely used today 2006 Sandumodified classification system EPIDEMIOLOGY [laryngeal-cleft.com]

Epidemiology, genetics, and syndromology, Teratology, 40, 3, (211-235), (2005). John B. Moeschler, Barbara R. Pober, Lewis B. Holmes and John M. [doi.org]

We aim to use the power of modern molecular genetics and clinical research to delineate the range of severity, natural history, molecular etiology, and pathophysiology of a number of congenital anomaly syndromes. [clinicaltrials.gov]

Pathophysiology Prior to 16 weeks' gestations, the amount of amniotic fluid is dependent on the transmembrane flow. After that, fetal urine production is the predominant mechanism that determines the amniotic fluid volume. [emedicine.medscape.com]

Kazunori Arita, Hiroshi Tokimura, Ryosuke Hanaya, Sei Sugata, Tomohide Akimitsu, Koji Iida, Kazuhiko Sugiyama and Kaoru Kurisu, Hypothalamic Hamartoma: Pathophysiology and Treatment( New Therapies in Pediatric Neurosurgery), Japanese Journal of Neurosurgery [doi.org]

This landmark study was begun in the fall of 1982 to test the benefits and risks of aspirin and beta carotene in the primary prevention of cardiovascular disease and cancer. [phs.bwh.harvard.edu]

Drug checking is an emerging harm reduction strategy that may help prevent overdose deaths. [phs.ca]

[…] abnormalities - the pituitary gland produces a number of hormones (chemical messages) polydactyly (extra digits) and syndactyly (webbing between digits) small/unusual growing nails bifid epiglottis - a split in a leaflet of tissue at the back of the throat that prevents [contact.org.uk]

1. Biesecker LG. Pallister-Hall Syndrome. 2000 May 25 [Updated 2017 May 18]. In: Pagon RA, Adam MP, Ardinger HH, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2017.
2. Azzam A, Lerner DM, Peters KF, Wiggs E, Rosenstein DL, Biesecker LG. Psychiatric and neuropsychological characterization of Pallister-Hall syndrome. Clin Genet. 2005;67(1):87-92.
3. Kuo JS, Casey SO, Thompson L, Truwit CL. Pallister-Hall syndrome: clinical and MR features. AJNR Am J Neuroradiol. 1999;20(10):1839-1841.
4. Biesecker LG, Graham JM. Pallister-Hall syndrome. J Med Genet. 1996;33(7):585-589.
5. Boudreau EA, Liow K, Frattali CM, et al. Hypothalamic hamartomas and seizures: distinct natural history of isolated and Pallister-Hall syndrome cases. Epilepsia. 2005;46:42-47.
6. Dericioglu N, Saygi S, Akalan N. Transcallosal endoscopic resection of hypothalamic hamartoma in a case with Pallister-Hall syndrome. Epileptic Disord. 2011;13(2):209-213.