Howel–Evans syndrome is an extremely rare condition involving thickening of the skin in the palms of the hands and the soles of the feet (

hyperkeratosis Hyperkeratosis is thickening of the stratum corneum (the outermost layer of the epidermis, or skin), often associated with the presence of an abnormal quantity of keratin,Kumar, Vinay; Fausto, Nelso; Abbas, Abul (2004) ''Robbins & Cotran Pathologi ...

). This familial disease is associated with a high lifetime risk of

esophageal cancer Esophageal cancer is cancer arising from the esophagus—the food pipe that runs between the throat and the stomach. Symptoms often include difficulty in swallowing and weight loss. Other symptoms may include pain when swallowing, a hoarse voice ...

. For this reason, it is sometimes known as tylosis with oesophageal cancer (TOC). The condition is inherited in an

autosomal dominant In genetics, dominance is the phenomenon of one variant (allele) of a gene on a chromosome masking or overriding the effect of a different variant of the same gene on the other copy of the chromosome. The first variant is termed dominant and t ...

manner, and it has been linked to a mutation in the '' RHBDF2'' gene. It was first described in 1958.

Presentation

This condition is inherited as an autosomal dominant syndrome and characterized by palmoplantar keratoderma, oral precursor lesions particularly on the gums (

leukoplakia Oral leukoplakia is a ''potentially malignant disorder'' affecting the oral mucosa. It is defined as "essentially an oral mucosal white lesion that cannot be considered as any other definable lesion." Oral leukoplakia is a white patch or plaque th ...

) and a high lifetime risk of esophageal cancer (95% develop esophageal cancer by the age of 65).Marger RS, Marger D (1993) Carcinoma of the esophagus and tylosis. A lethal genetic combination. Cancer 72(1):17–19 Relapsing cutaneous horns of the lips has been reported in this condition.Baykal C, Savci N, Kavak A, Kurul S (2002) Palmoplantar keratoderma and oral leucoplakia with cutaneous horn of the lips. Br J Dermatol 146(4):680–683 There are several types of this condition have been described – epidermolytic (Vörner type) and non-epidermolytic. Another classification divides these into an early onset type (type B) which occurs in the first year of life and is usually benign and a type A tylosis which occurs between the ages of 5 and 15 years and is strongly associated with esophageal cancer.Maillefer RH, Greydanus MP (1999) To B or not to B: is tylosis B truly benign? Two North American genealogies. Am J Gastroenterol 94(3):829–834

Cytoglobin Cytoglobin is the protein product of CYGB, a human and mammalian gene. Cytoglobin is a globin molecule ubiquitously expressed in all tissues and most notably utilized in marine mammals. It was discovered in 2001 and named cytoglobin in 2002. It i ...

gene expression in oesophageal biopsies is significantly reduced (70% reduction) in this condition.McRonald FE, Liloglou T, Xinarianos G, Hill L, Rowbottom L, Langan JE, Ellis A, Shaw JM, Field JK, Risk JM (2006) Down-regulation of the cytoglobin gene, located on 17q25, in tylosis with oesophageal cancer (TOC): evidence for trans-allele repression. Hum Mol Genet 15(8):1271–1277 The mechanism of this change is not known.

Genetics

The gene responsible is '' RHBDF2'' (Rhomboid family member 2), which is located on the long arm of chromosome 17 (at 17q25).Saarinen S, Vahteristo P, Lehtonen R, Aittomäki K, Launonen V, Kiviluoto T, Aaltonen LA (2012) Analysis of a Finnish family confirms RHBDF2 mutations as the underlying factor in tylosis with esophageal cancer. Fam Cancer The mutation responsible for the disease was detected in Finnish, German, UK and US families. The RHBDF2 protein is a member of the intramembranous

serine protease Serine proteases (or serine endopeptidases) are enzymes that cleave peptide bonds in proteins. Serine serves as the nucleophilic amino acid at the (enzyme's) active site. They are found ubiquitously in both eukaryotes and prokaryotes. ...

s. It is thought to play an important role in the

epithelial Epithelium or epithelial tissue is one of the four basic types of animal tissue, along with connective tissue, muscle tissue and nervous tissue. It is a thin, continuous, protective layer of compactly packed cells with a little intercellula ...

response to injury in the

esophagus The esophagus (American English) or oesophagus (British English; both ), non-technically known also as the food pipe or gullet, is an organ in vertebrates through which food passes, aided by peristaltic contractions, from the pharynx to the ...

and skin. ''RHBDF2'' is involved in the regulation of the secretion of several ligands of the

epidermal growth factor receptor The epidermal growth factor receptor (EGFR; ErbB-1; HER1 in humans) is a transmembrane protein that is a receptor for members of the epidermal growth factor family (EGF family) of extracellular protein ligands. The epidermal growth factor recept ...

Molecular biology

The rhomboid proteases – the first known intramembranous serine proteasesFreeman M (2009) Rhomboids: 7 years of a new protease family. Semin Cell Dev Biol 20(2):231–239 – were discovered in 1988.Mayer U, Nüsslein-Volhard C (1988) A group of genes required for pattern formation in the ventral

ectoderm The ectoderm is one of the three primary germ layers formed in early embryonic development. It is the outermost layer, and is superficial to the mesoderm (the middle layer) and endoderm (the innermost layer). It emerges and originates from t ...

of the ''Drosophila'' embryo. Genes Dev. 1988 Nov;2(11):1496–511 The first rhomboid protease was cloned in 1990Bier E, Jan LY, Jan YN (1990) Rhomboid, a gene required for dorsoventral axis establishment and peripheral nervous system development in ''Drosophila melanogaster''. Genes Dev 4(2):190–203 Rhomboid proteases have a core of six transmembrane helices with the active site residues lying in a hydrophilic cavity. Rhomboid family members are widely conserved and found in all three kingdoms of life.Koonin EV, Makarova KS, Rogozin IB, Davidovic L, Letellier MC, Pellegrini L (2003) The rhomboids: a nearly ubiquitous family of intramembrane serine proteases that probably evolved by multiple ancient horizontal gene transfers. Genome Biol. 2003; 4(3):R19 RHBDF2 associates with the rhomboid like protease 2 ( RHBDL2) and inhibits its activity. Mutations in RHBDF2 inhibit

tumour necrosis factor The tumor necrosis factor (TNF) superfamily is a protein superfamily of type II transmembrane proteins containing TNF homology domain and forming trimers. Members of this superfamily can be released from the cell membrane by extracellular pro ...

alpha. RHBDL2 also acts on

Epidermal growth factor Epidermal growth factor (EGF) is a protein that stimulates cell growth and differentiation by binding to its receptor, EGFR. Human EGF is 6-k Da and has 53 amino acid residues and three intramolecular disulfide bonds. EGF was originally descr ...

and EphrinB3.

Thrombomodulin Thrombomodulin (TM), CD141 or BDCA-3 is an integral membrane protein expressed on the surface of endothelial cells and serves as a cofactor for thrombin. It reduces blood coagulation by converting thrombin to an anticoagulant enzyme from a procoag ...

– a membrane glycoprotein – is upregulated in neoepidermis during cutaneous wound healing. RHBDL2 cleaves thrombomodulin at the transmembrane domain and causes the release of soluble thrombomodulin.

Other associations

RHBDF2 may also play a role in ovarian epithelial cancer.Wojnarowicz PM, Provencher DM, Mes-Masson A-M, Tonin PN (2012) Chromosome 17q25 genes, RHBDF2 and CYGB, in ovarian cancer. Int J Oncol 40 (6) 1865-1880 Doi: 10.3892/ijo.2012.1371 Possible associations with

gastric cancer Stomach cancer, also known as gastric cancer, is a cancer that develops from the lining of the stomach. Most cases of stomach cancers are gastric carcinomas, which can be divided into a number of subtypes, including gastric adenocarcinomas. Lymph ...

Wagle PK, Shetty TS, Darbari A, Tapia AA, Katrak MP, Joshi RM (2002) Carcinoma of stomach in a patient with familial tylosis. Indian J Gastroenterol 21(6):227Murata I, Ogami Y, Nagai Y, Furumi K, Yoshikawa I, Otsuki M (1998) Carcinoma of the stomach with hyperkeratosis palmaris et plantaris and acanthosis of the esophagus. Am J Gastroenterol 93(3):449–451 and

lung cancer Lung cancer, also known as lung carcinoma (since about 98–99% of all lung cancers are carcinomas), is a malignant lung tumor characterized by uncontrolled cell growth in tissue (biology), tissues of the lung. Lung carcinomas derive from tran ...

Grundmann JU, Weisshaar E, Franke I, Bonnekoh B, Gollnick H (2003) Lung carcinoma with congenital plantar keratoderma as a variant of Clarke-Howel-Evans syndrome. Int J Dermatol 42(6):461–463Nomori H, Horio H, Iga R, Fuyuno G, Kobayashi R, Morinaga S (1996) Squamous cell carcinoma of the lung associated with palmo-plantar hyperkeratosis. Nihon Kyobu Shikkan Gakkai Zasshi 34(1):76–79Khanna SK, Agnone FA, Leibowitz AI, Raschke RA, Trehan M (1993) Nonfamilial diffuse palmoplantar keratoderma associated with bronchial carcinoma. J Am Acad Dermatol 28(2 Pt 2):295–297Murata Y, Kumano K, Tani M, Saito N, Kagotani K (1988) Acquired diffuse keratoderma of the palms and soles with bronchial carcinoma: report of a case and review of the literature. Arch Dermatol 124(4):497–498 have been suggested. Other possible associations include corneal defects, congenital

pulmonary stenosis Pulmonic stenosis, is a dynamic or fixed obstruction of flow from the right ventricle of the heart to the pulmonary artery. It is usually first diagnosed in childhood. Signs and symptoms Cause Pulmonic stenosis is usually due to isolated valvula ...

,Wong ML, Tay JS (1991) Congenital heart disease in tylosis: case report. J Singapore Paediatr Soc 33(1–2):45–48 total anomalous pulmonary venous connectionHoeger PH, Yates RW, Harper JI (1998) Palmoplantar keratoderma associated with congenital heart disease. Br J Dermatol 138(3):506–509

deafness Deafness has varying definitions in cultural and medical contexts. In medical contexts, the meaning of deafness is hearing loss that precludes a person from understanding spoken language, an audiological condition. In this context it is written ...

Fitzgerald DA, Verbov JL (1996) Hereditary palmoplantar keratoderma with deafness. Br J Dermatol 134(5):939–942 and

optic atrophy Optic neuropathy is damage to the optic nerve from any cause. The optic nerve is a bundle of millions of fibers in the retina that sends visual signals to the brain. Damage and death of these nerve cells, or neurons, leads to characteristic featu ...

.Dimsdale H (1949) Hereditary optic atrophy in family with keratodermia palmaris et plantaris (tylosis). Proc R Soc Med 42(10):796

Related genes

A related gene – Rhomboid domain containing 2 ( RHBDD2) – appears to be important in

breast cancer Breast cancer is cancer that develops from breast tissue. Signs of breast cancer may include a lump in the breast, a change in breast shape, dimpling of the skin, milk rejection, fluid coming from the nipple, a newly inverted nipple, or a re ...

.Abba MC, Lacunza E, Nunez MI, Colussi A, Isla-Larrain M, Segal-Eiras A, Croce MV, Aldaz CM (2009) Rhomboid domain containing 2 (RHBDD2): a novel cancer-related gene over-expressed in breast cancer. Biochim Biophys Acta 1792(10):988–997 A second related gene – rhomboid family 1 ( RHBDF1) – appears to be important in head and neck cancer.Zou H, Thomas SM, Yan ZW, Grandis JR, Vogt A, Li LY (2009) Human rhomboid family-1 gene RHBDF1 participates in GPCR-mediated transactivation of EGFR growth signals in head and neck squamous cancer cells. FASEB J 23(2):425–432 A third member of this family – RHBDD1 – cleaves Bcl-2-interacting killer ( BIK) – a

proapoptotic Apoptosis (from grc, ἀπόπτωσις, apóptōsis, 'falling off') is a form of programmed cell death that occurs in multicellular organisms. Biochemical events lead to characteristic cell changes ( morphology) and death. These changes inclu ...

member of the B cell lymphoma 2 (

Bcl-2 Bcl-2 (B-cell lymphoma 2), encoded in humans by the ''BCL2'' gene, is the founding member of the Bcl-2 family of regulator proteins that regulate cell death (apoptosis), by either inhibiting (anti-apoptotic) or inducing (pro-apoptotic) apoptosis. ...

) family.Wang Y, Guan X, Fok KL, Li S, Zhang X, Miao S, Zong S, Koide SS, Chan HC, Wang L (2008) A novel member of the Rhomboid family, RHBDD1, regulates BIK-mediated apoptosis. Cell Mol Life Sci 65(23):3822–3829 These proteins may also have a role in

diabetes Diabetes, also known as diabetes mellitus, is a group of metabolic disorders characterized by a high blood sugar level ( hyperglycemia) over a prolonged period of time. Symptoms often include frequent urination, increased thirst and increased ap ...

.Walder K, Kerr-Bayles L, Civitarese A, Jowett J, Curran J, Elliott K, Trevaskis J, Bishara N, Zimmet P, Mandarino L, Ravussin E, Blangero J, Kissebah A, Collier GR (2005) The mitochondrial rhomboid protease PSARL is a new candidate gene for type 2 diabetes. Diabetologia 48(3):459–468

Diagnosis

Differential diagnosis

The differential diagnosis is quite extensive and includesItin PH, Fistarol SK (2005) Palmoplantar keratodermas. Clin Dermatol 23(1):15–22Ratnavel RC, Griffiths WA (1997) The inherited palmoplantar keratodermas. Br J Dermatol 137(4):485–490

Treatment

Systemic retinoids are the drugs used for tylosis.

Terminology

The condition is also referred to by several other names, including "familial keratoderma with carcinoma of the esophagus," "focal non-epidermolytic palmoplantar keratoderma with carcinoma of the esophagus," "Palmoplantar ectodermal dysplasia type III," "palmoplantar keratoderma associated with esophageal cancer," "tylosis"James, William; Berger, Timothy; Elston, Dirk (2005). ''Andrews' Diseases of the Skin: Clinical Dermatology''. (10th ed.). Saunders. .Freedberg, et al. (2003). ''Fitzpatrick's Dermatology in General Medicine''. (6th ed.). McGraw-Hill. . and "tylosis–esophageal cancer"

References

External links

{{DEFAULTSORT:Howel-Evans syndrome Palmoplantar keratodermas Rare cancers Genetic disorders with OMIM but no gene Syndromes